High affinity small molecule C5a receptor modulators

ABSTRACT

This invention relates to low molecular weight, non-peptidic, non-peptidomimetic, organic molecules that act as modulators of mammalian complement C5a receptors, preferably ones that act as high affinity C5a receptor ligands and also to such ligands that act as antagonists or inverse agonists of complement C5a receptors. Preferred compounds of the invention possess some or all of the following properties in that they are: 1) multi-aryl in structure, 2) heteroaryl in structure, 3) a pharmaceutically acceptable oral dose can provide a detectable in vitro effect, 4) comprise fewer than four or preferably no amide bonds, and 5) capable of inhibiting leukocyte chemotaxis at nanomolar or sub-nanomolar concentrations. 
     This invention also relates to pharmaceutical compositions comprising such compounds and the use of such compounds in treating a variety of inflammatory and immune system disorders. Additionally, this invention relates to the use such compounds as probes for the localization of C5a receptors.

This application is a divisional of U.S. Ser. No. 10/461,311 filed Jun.12, 2003, now U.S. Pat. No. 6,884,815, which application was adivisional of U.S. Ser. No. 09/672,071 filed Sep. 28, 2000, now issuedas U.S. Pat. No. 6,723,743, which application claims priority from thefollowing five U.S. Provisional applications: 1) application No.60/156,390, filed Sep. 28, 1999; 2) application No. 60/202,749, filedMay 8, 2000; 3) application No. 60/212,449, filed Jun. 16, 2000; 4)application No. 60/221,787, filed Jul. 31, 2000; and 5) application No.60/224,036, filed Aug. 9, 20000, all of which five applications whichare incorporated herein by reference for their teachings with regard toC5a receptor ligands, including arylimidazoles, arylpyridyls,aryl-substituted cycloalkylimidazoles, arylpyrazoles, andbenzimidazoles.

BACKGROUND

1. Field of the Invention

This invention relates to low molecular weight, non-peptidic,non-peptidomimetic, organic molecules that act as modulators ofmammalian complement C5a receptors, preferably ones that act as highaffinity C5a receptor ligands. The invention also relates to suchligands that act as antagonists (including inverse agonists) ofcomplement C5a receptors, preferably human C5a receptors. This inventionalso relates to pharmaceutical compositions comprising such compounds.It further relates to the use of such compounds in treating a variety ofinflammatory and immune system disorders. Additionally, this inventionrelates to the use such compounds as probes for the localization of C5areceptors.

2. Background of the Invention

C5a, a 74 amino acid peptide, is generated in the complement cascade bythe cleavage of the complement protein C5 by the complement C5convertase enzyme. C5a has both anaphylatoxic (e.g., bronchoconstrictingand vascular spasmogenic) and chemotactic effects. Therefore, it isactive in engendering both the vascular and cellular phases ofinflammatory responses. Because it is a plasma protein and, therefore,generally almost instantly available at a site of an inciting stimulus,it is a key mediator in terms of initiating the complex series of eventsthat results in augmentation and amplification of an initialinflammatory stimulus. The anaphylatoxic and chemotactic effects of theC5a peptide are believed to be mediated through its interation with theC5a receptor (CD88 antigen), a 52 kD membrane bound G-protein coupledreceptor (GPCR). C5a is a potent chemoattractant for polymorphonuclearleukocytes, bringing neutrophils, basophils, eosinophils and monocytesto sites of inflammation and/or cellular injury. C5a is one of the mostpotent chemotactic agents known for a wide variety of inflammatory celltypes. C5a also “primes” or prepares neutrophils for variousantibacterial functions, e.g., phagocytosis. Additionally, C5astimulates the release of inflammatory mediators (e.g., histamines,TNF-α, IL-1, IL-6, IL-8, prostaglandins, and leukotrienes) and therelease of lysosomal enzymes and other cytotoxic components fromgranulocytes. Among its other actions, C5a also promotes the productionof activated oxygen radicals and the contraction of smooth muscle.

Considerable experimental evidence implicates increased levels of C5a ina number of autoimmune diseases and inflammatory and related disorders.

Antagonists that block the binding of C5a to its receptor or otheragents, including inverse agonists, which modulate signal transductionassociated with C5a-receptor interactions, can inhibit the pathogenicevents, including chemotaxis, associated with anaphylatoxin activitycontributing to such inflammatory and autoimmune conditions. Despitemany attempts, no one has previously been able to provide any smallmolecule (less than 700 Daltons MW, or amu) non-peptide,non-peptidomimetic, non-peptoid, C5a antagonist that is essentially freeof agonist activity at the C5a receptor and that exhibits a bindingaffinity for the C5a receptor of less than 1 micromolar, and preferablyless than 100 nanomolar.

3. Description of Related Art

Certain modified C5a peptides (i.e., modifications of C5a) have beenidentified as partial C5a antagonists and have been shown to block anumber of C5a mediated actions including neutrophil chemotaxis,neutropenia and superoxide formation. Various C5a peptidomimeticcompounds have also been reported as modulating C5a activity, includingcyclic peptoids (a peptoid is a peptidomimetic compound comprising anoligomeric assemblage of naturally occurring amino acids that have beenN-substituted). Typically these C5a modulatory compounds exhibit amolecular weight greater than 500 Daltons, and generally greater than700 Daltons.

SUMMARY OF THE INVENTION

The present invention provides novel compounds that are small moleculeC5a receptor antagonists that are non-peptide, non-peptidomimetic, andare preferably free of C5a receptor agonist activity, which compoundsexhibit high affinity for the C5a receptor, i.e., an affinity constantfor binding to the C5a receptor of less than 1 micromolar. Highlypreferred compounds exhibit very high affinity for the C5a receptor,i.e., an affinity constant for binding to the C5a receptor of less than100 nanomolar. Preferred compounds are C5a receptor antagonists(including inverse agonists). Preferred antagonists exhibit anantagonist EC₅₀ (which as used herein includes IC₅₀) of less than 1micromolar, preferably less than 100 nanomolar, in an assay of C5amediated chemotaxis. Preferred C5a receptors are mammalian, preferablyprimate receptors, including human C5a receptors, and may either becloned, recombinantly expressed receptors or naturally expressedreceptors. In certain preferred embodiments, compounds of the inventionexhibit an affinity for human C5a receptors that is higher than forrodent C5a receptors, preferably at least five times higher, morepreferably ten times higher.

The compounds of the present invention do not interact with dopaminereceptors with even moderate affinity, i.e., they do not bind todopamine receptors with K_(i) values of less than 100 micromolar.Preferred compounds of the invention do not bind to any naturallyoccurring receptors other than C5a receptors with high affinity, andpreferably they do not bind to any naturally occurring receptors otherthan C5a receptors with even moderate affinity.

In certain embodiments these compounds also possess one or more, andpreferably two or more, three or more, four or more, or all of thefollowing properties in that they are: 1) multi-aryl in structure(having a plurality of un-fused or fused aryl groups), 2) heteroaryl instructure, 3) orally available in vivo (such that a sub-lethal orpreferably a pharmaceutically acceptable oral dose can provide adetectable in vivo effect such as a reduction of C5a-inducedneutropenia), 4) comprised of fewer than four, preferably fewer thanthree, or fewer than two, or no amide bonds, and 5) capable ofinhibiting leukocyte chemotaxis at nanomolar concentrations andpreferably at sub-nanomolar concentrations.

In a highly preferred aspect, the invention provides non-peptidic,non-peptidomimetic, low molecular weight compounds that act as highaffinity antagonists of the human C5a receptor. Specifically exemplifiedrepresentative compounds include, but are not limited to optionallysubstituted arylimidazoles (i.e. imidazoles having one or more ringsubstituents of optionally substituted carbocyclic aryl or optionallysubstituted heteroaryl), optionally substituted arylpyridyls (i.e.pyridyls having one or more ring substituents of optionally substitutedcarbocyclic aryl or optionally substituted heteroaryl), optionallysubstituted aryl-substituted cycloalkylimidazoles (i.e.cycloalkylimidazoles having one or more ring substituents of optionallysubstituted carbocyclic aryl or optionally substituted heteroaryl),optionally substituted arylpyrazoles (i.e. pyrazoles having one or morering substituents of optionally substituted carbocyclic aryl oroptionally substituted heteroaryl), optionally substitutedbenzimidazoles, optionally substituted aryl-substitutedtetrahydroisoquinolines (i.e. tetrahydroisoquinolines having one or morering substituents of optionally substituted carbocyclic aryl oroptionally substituted heteroaryl), and optionally substituted biarylcarboxamides (i.e. a carboxamide that has one or more optionallysubstituted bi-carboxylic aryl or heteroaryl substituents). Novelintermediates useful for synthesizing compounds of the invention arealso provided.

Preferred compounds of the invention are compounds of Formula I, shownbelow, that bind specifically, and preferably with high affinity, to C5areceptors.

The invention also provides pharmaceutical compositions comprisingcompounds of the invention, including those of Formula I, includingotppinally substituted arylimidazoles, optionally substitutedarylpyridyls, optionally substituted aryl-substitutedcycloalkylimidazoles, optionally substituted arylpyrazoles, optionallysubstituted benzimidazoles, optionally substituted aryl-substitutedtetrahydroisoquinolines, and optionally substituted biaryl carboxamides.The C5a receptor antagonist compounds described herein are particularlyuseful in the treatment of C5a-mediated inflammation, e.g., inflammationassociated with various inflammatory and immune system disorders. Theinvention further comprises a method of treating a patient in need ofsuch anti-inflammatory treatment or immune treatment an effective amountof a compound of the invention, e.g. an amount of a compound of theinvention sufficient to yield a plasma concentration of the compound (orits active metabolite, if a pro-drug) high enough to inhibit white bloodcell (e.g., neutrophil) chemotaxis in vitro. Treatment of humans,domesticated companion animals (pets) or livestock animals sufferingsuch conditions with an effective amount of a compound of the inventionis contemplated by the invention. For treating non-human animals of anyparticular species, a compound exhibiting high affinity for the C5areceptor of that particular species is preferred.

In a separate aspect, the invention provides methods of using compoundsof the invention as positive controls in assays for receptor activityand using appropriately labeled compounds of the invention as probes forthe localization of receptors, particularly C5a receptors, e.g., intissue sections (e.g., via autoradiography) or in vivo (e.g., viapositron emission tomography, PET, or single positron emission computedtomography, SPECT, scanning and imaging).

The invention provides compounds and compositions that are useful asinhibitors of C5a-mediated chemotaxis (e.g., they may be used asstandards in assays of such chemotaxis). The invention additionallycomprises methods of inhibiting C5a-mediated cellular chemotaxis,preferably leukocyte (e.g., neutrophil) chemotaxis. These methodscomprise contacting white blood cells, particularly primate white bloodcells, especially human white blood cells, with one or more compounds ofthe invention. Preferably the concentration is sufficient to inhibitchemotaxis of white blood cells in an in vitro chemotaxis assay, so thatthe levels of chemotaxis observed in a control assay (e.g., one to whicha compound of the invention has not been added) are significantly higher(significantly here measured as p≦0.05 using a conventional parametricstatistical analysis method such as a student's T-test) than the levelsobserved in an assay to which a compound of the invention has beenadded.

Accordingly, a broad aspect of the invention is directed to non-peptidicorganic (carbon-containing) molecules, having a molecular mass of lessthan 700 amu, that exhibit C5a antagonist activity or C5a inverseagonist activity with an EC₅₀ of less than 500 nM in an assay of C5amediated leukocyte chemotaxis.

More particularly the invention includes compounds of Formula I,

Formula I

wherein:

-   AR1 and AR2 are independently carbocyclic aryl or heteroaryl;-   LIP represents an alkyl, carbocyclic aryl, heteroaryl, or arylalkyl;-   A is oxygen or nitrogen;-   d₁ represents the distance between A and the geometric center of AR1    and is between 3 and 6 angstroms in at least one energetically    accessible conformer of the compound;-   d₂ represents the distance between A and the geometric center of AR2    and is between 5 and 10 angstroms in at least one energetically    accessible conformer of the compound; and

d₃ represents the distance between A and the nearest atom of LIP and isbetween 3 and 6 angstroms in at least one energetically accessibleconformer of the compound. Preferred compounds of Formula I exhibitantagonist (including inverse agonist) activity at C5a Receptors, andessentially no or little agonist activity at this receptor. Preferablysuch compounds contain one or more heteroaryl rings.

Preferred compounds of the invention exhibit good activity in standardin vitro C5 receptor mediated chemotaxis assay, specifically the assayas specified in Example 12, which follows and is defined below.Alternative preferred assays include the calcium mobilization assay.Preferred compounds of the invention exhibit an EC₅₀ of about 500 nM orless in such a standard C5a mediated chemotaxis assay, more preferablyan EC₅₀ of about 200 nM or less in such a standard C5a mediatedchemotaxis assay, still more preferably an EC₅₀ of about 100, 50, 25 and10 nM in such a standard C5a mediated chemotaxis assay, even morepreferably an EC₅₀ of about 5 nM in such a standard C5a mediatedchemotaxis assay.

The invention includes additional methods such as methods for localizingC5a receptors in tissue section samples, comprising cotacting a tissuesample with detectably labelled one or more compounds of the inventionthat are preferably detectably labeled, optionally washing the contactedtissue sample, and detecting the bound compound associated with thetissue sample. Suitable detectable labels include e.g. ¹²⁵I, tritium,³²P, ⁹⁹Tc or the like. A variety of detection methods could be employedinclude single emission photono computed tomography (“SPECT”).

Other aspects of the invention are discussed infra

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is the sequence of SEQ ID NO-1.

DETAILED DESCRIPTION OF THE INVENTION

Preferred compounds of the invention include carbon-containing moleculesthat comprise:

i) having a molecular mass of less than 700 amu;

ii) that is nonpeptidic;

iii) that exhibits C5a antagonist activity or C5a inverse agonistactivity with an EC₅₀ of less than 500 nM in an assay of C5a mediatedleukocyte chemotaxis; and

iv) exhibits less than 10% intrinsic agonist activity in an assay ofleukocyte chemotaxis.

Among such compounds, particularly preferred are those that contain oneor more heteroaryl and/or carbocyclic rings. For example, preferred arecompounds of the following formula:

-   AR1 and AR2 are independently optionally substituted carbocyclic    aryl or optionally substituted heteroaryl;-   LIP represents an optionally substituted alkyl, optionally    substituted carbocyclic aryl, optionally substituted heteroaryl, or    optionally substituted arylalkyl;-   A is oxygen or nitrogen;-   d₁ represents the distance between A and the geometric center of AR1    and is between 3 and 6 angstroms in at least one energetically    accessible conformer of the compound;-   d₂ represents the distance between A and the geometric center of AR2    and is between 5 and 10 angstroms in at least one energetically    accessible conformer of the compound; and-   d₃ represents the distance between A and the nearest atom of LIP and    is between 3 and 6 angstroms in at least one energetically    accessible conformer of the compound.

Preferred compounds of the invention also include heterocycles of thefollowing formula II:

or a pharmaceutically acceptable salt thereof, wherein the compoundexhibits an EC₅₀ of 1 uM or less in an assay of C5a mediated chemotaxis,wherein:the ring system represented by

is a 5 to 7 membered heterocycle that may be either aromatic orpartially unsaturated;X is N, C, or CR₇, wherein R₇ is hydrogen, hydroxy, halogen, amino,cyano, nitro, optionally substituted haloalkyl, optionally substitutedalkoxy, optionally substituted mono- or dialkylamino, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl or optionally substituted (cycloalkyl)alkyl;

-   Y is N or CH;-   n is 0, 1, or 2;-   m is 0, 1, or 2;-   R and R₁ are independently chosen from hydrogen, hydroxy, halogen,    amino, cyano, nitro, optionally substituted haloalkyl, optionally    substituted alkoxy, optionally substituted mono- or dialkylamino,    optionally substituted alkyl, optionally substituted alkenyl,    optionally substituted alkynyl, optionally substituted cycloalkyl,    optionally substituted (cycloalkyl)alkyl,    -   optionally substituted carbocyclic aryl, optionally substituted        arylalkyl, optionally substituted heteroaryl or heteroalicyclic        group having from 1 to 3 rings, 3 to 8 members in each ring and        from 1 to 3 heteroatoms;-   R₂, R₃, R_(3A), R₅ and R₆ are independently selected from hydrogen,    hydroxy, halogen, amino, cyano, nitro, optionally substituted    haloalkyl, optionally substituted alkoxy, optionally substituted    mono- or dialkylamino, optionally substituted alkyl, optionally    substituted alkenyl, optionally substituted alkynyl, optionally    substituted cycloalkyl, and optionally substituted    (cycloalkyl)alkyl;-   When n is 0, R₁ and R₃ may be joined to form a cycloalkyl or    heterocycloalkyl ring, each of which may be optionally substituted;-   When n is 1, R and R₃ may be joined to form a cycloalkyl or    heterocycloalkyl ring, each of which may be optionally substituted;-   R₄ is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of    which may be optionally substituted; or-   R₄ is optionally substituted carbocyclic aryl, optionally    substituted arylalkyl, optionally substituted heteroaryl or    heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in    each ring and from 1 to 3 heteroatoms; and-   Ar₁ and Ar₂ are independently optionally substituted carbocyclic    aryl, optionally substituted arylalkyl, optionally substituted    heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8    members in each ring and from 1 to 3 heteroatoms.

Preferred compounds of the above Formula II include those compoundswherein:

-   R and R₁ are independently selected from    -   i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or        dialkylamino, cyano, nitro, haloalkyl, and    -   ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl,        each of which may be unsubstituted or substituted by one or more        of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,        haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or        dialkylamino,    -   iii) phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl,        thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,        triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of        which may be optionally substituted or substituted with up to        four groups independently selected from halogen, nitro, cyano,        trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,        alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or        dialkylamino;-   R₂, R₃, R_(3A), R₅, and R₅ are independently selected from    -   i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or        dialkylamino, cyano, nitro, haloalkyl, and    -   ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl,        each of which may be unsubstituted or substituted by one or more        of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,        haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or        dialkylamino:-   R₇ is hydrogen, hydroxy, halogen, amino, cyano, nitro, or haloalkyl,    or-   R₇ is alkoxy, mono- or dialkylamino, alkyl, alkenyl, alkynyl or    (cycloalkyl)alkyl, each of which may be unsubstituted or substituted    by one or more of halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and    mono- or dialkylamino;-   When n is 0, R₃ and R₃ may be joined to form a cycloalkyl or    heterocycloalkyl ring, each of which may be unsubstituted or    substituted with one or more substituents selected from halogen,    nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,    acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or    dialkylamino;-   When n is 1, R and R₃ may be joined to form a cycloalkyl or    heterocycloalkyl ring, each of which may be unsubstituted or    substituted with one or more substituents selected from halogen,    nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,    acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or    dialkylamino;-   R₄ is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, each    of which may be unsubstituted or substituted with    -   one or more substituents selected from halogen, nitro, cyano,        trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,        alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or        dialkylamino; or-   R₄ is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl,    pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,    pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,    benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino,    carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or    dialkylaminocarbonyl, N-alkylsulfonylaminocarbonyl, 1-azetidinyl,    1-pyrrolidinyl, and 1-piperidyl; or-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and        mono- or dialkylamino; and

-   Ar₁ and Ar₂ are independently chosen from

-   i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl,    pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,    pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,    benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino,    carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or    dialkylaminocarbonyl, N-alkylsulfonylaminocarbonyl, 1-azetidinyl,    1-pyrrolidinyl, and 1-piperidyl, and

-   ii) bicyclic oxygen-containing groups of the formula:

-   -   wherein R_(B) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and        mono- or dialkylamino.

Additional preferred compounds of the above formula II include thosewherein

-   R and R₁ are independently selected from    -   i) hydrogen, halogen, hydroxy, amino, C₁–C₆ alkoxy, mono- or        di(C₁–C₆)alkylamino, cyano, nitro, haloalkyl, and    -   ii) C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl,        and (C₃–C₈)cycloalkyl) C₁–C₃ alkyl, each of which may be        unsubstituted or substituted by one or more of halogen, nitro,        cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,        acetoxy, alkoxy, amino, and mono- or di(C₁–C₆)alkylamino,    -   iii) phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl,        thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,        triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of        which may be optionally substituted or substituted with up to        four groups independently selected from halogen, nitro, cyano,        trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,        C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino,        and mono- or di(C₁–C₆)alkylamino;-   When n is 0, R₁ and R₃ may be joined to form a C₃–C₈ cycloalkyl or    C₃–C₈ heterocycloalkyl ring, each of which may be unsubstituted or    substituted with one or more substituents selected from halogen,    nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,    acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy,    amino, mono- or di(C₁–C₆)alkylamino;-   When n is 1, R and R₃ may be joined to form a C₃–C₈ cycloalkyl or    C₃–C₈ heterocycloalkyl ring, each of which may be unsubstituted or    substituted with one or more substituents selected from halogen,    nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,    acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy,    amino, and mono- or di(C₁–C₆)alkylamino;-   R₂, R₃, R_(3A), R₅, and R₆ are independently selected from    -   i) hydrogen, halogen, hydroxy, amino, C₁–C₆ alkoxy, mono- or        di(C₁–C₆)alkylamino, cyano, nitro, haloalkyl, and    -   ii) C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl,        and (C₃–C₈ cycloalkyl) C₁–C₃ alkyl, each of which may be        unsubstituted or substituted by one or more of halogen, nitro,        cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,        acetoxy, C₁–C₆ alkoxy, amino, mono- or di(C₁–C₆)alkylamino;-   R₇ is hydrogen, hydroxy, halogen, amino, cyano, nitro, or haloalkyl,    R₇ is alkoxy, mono- or di(C₁–C₆)alkylamino, C₁–C₆ alkyl,    C₂–C₆alkenyl, C₂–C₆ alkynyl or (C₃–C₈cycloalkyl) C₁–C₃ alkyl, each    of which may be unsubstituted or substituted by one or more of    halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,    hydroxy, acetoxy, C₁–C₆ alkoxy, amino, and mono- or    di(C₁–C₆)alkylamino;-   R₄ is C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl,    (C₃–C₈ cycloalkyl) C₁–C₃ alkyl, each of which may be unsubstituted    or substituted with one or more substituents selected from halogen,    nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,    acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy,    amino, and mono- or di(C₁–C₆)alkylamino; or-   R₄ is phenyl, phenyl(C₁–C₄)alkyl, chromanyl, pyrrolyl, furanyl,    thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,    pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,    benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino,    mono- or di(C₁–C₆)alkylamino, carboxylic acid, esters of carboxylic    acids, aminocarbonyl, mono or di(C₁–C₆)alkylaminocarbonyl,    N—(C₁–C₆)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,    and 1-piperidyl; or-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,        C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino; and

-   Ar₁ and Ar₂ are independently chosen from phenyl,    phenyl(C₁–C₄)alkyl, chromanyl, pyrrolyl, furanyl, thienyl,    pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,    pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,    benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino,    mono- or di(C₁–C₆)alkylamino, carboxylic acid, esters of carboxylic    acids, aminocarbonyl, mono or di(C₁–C₆)alkylaminocarbonyl,    N—(C₁–C₆)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,    and 1-piperidyl; and

-   ii) bicyclic oxygen-containing groups of the formula:

-   -   wherein R_(B) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,        C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino.

Still additional preferred compounds of the above formula II includethose compounds of the following formula:

and additionally include those compounds of the following formula:

-   m is 0, 1, or 2;-   R₁ is chosen from hydrogen, hydroxy, halogen, amino, cyano, nitro,    haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted    alkyl, optionally substituted alkenyl, optionally substituted    alkynyl, optionally substituted cycloalkyl, optionally substituted    (cycloalkyl)alkyl,    -   optionally substituted carbocyclic aryl, optionally substituted        arylalkyl, optionally substituted heteroaryl or heteroalicyclic        group having from 1 to 3 rings, 3 to 8 members in each ring and        from 1 to 3 heteroatoms;-   R₂, R₃, R_(3A), R₅, and R₆ are independently selected from hydrogen,    hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or    dialkylamino, optionally substituted alkyl, optionally substituted    alkenyl, optionally substituted alkynyl, optionally substituted    cycloalkyl, and optionally substituted (cycloalkyl)alkyl;-   R₄ is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of    which may be optionally substituted; or-   R₄ is optionally substituted carbocyclic aryl, optionally    substituted arylalkyl, optionally substituted heteroaryl or    heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in    each ring and from 1 to 3 heteroatoms; and-   Ar₁ and Ar₂ are independently optionally substituted carbocyclic    aryl, optionally substituted arylalkyl, optionally substituted    heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8    members in each ring and from 1 to 3 heteroatoms.

Additional preferred compounds of the above formula II include thosecompounds of the following formula:

wherein:

-   R₁ is hydrogen, C₁–C₇ alkyl, halogen or phenyl optionally    substituted with C₁–C₆ alkyl, C₁–C₆ alkoxy, halogen, hydroxy, amino,    or mono- or di(C₁–C₆)alkylamino;-   R₂ is C₁–C₈ alkyl or C₃–C₈ cycloalkyl; and-   R₃ is hydrogen or C₁–C₇ alkyl.

Additional preferred compounds of the above formula II include thosecompounds of the following formula:

wherein:

-   Ar₁ is phenyl, phenylalkyl, thienyl, imidazolyl, pyridyl, pyrimidyl,    benzodioxinyl, benzodioxolyl, each of which may be optionally    substituted or substituted with up to four groups independently    selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino;-   Ar₂ is defined as in Claim 2;-   R₁ is hydrogen, C₁–C₇ alkyl, halogen or phenyl optionally    substituted with C₁–C₆ alkyl, C₁–C₆ alkoxy, halogen, hydroxy, amino,    or mono- or di(C₁–C₆)alkylamino;-   R₂ is C₁–C₈ alkyl or C₃–C₈ cycloalkyl; and-   R₃ is hydrogen or C₁–C₇ alkyl; and-   R₄ is C₁–C₈ alkyl, C₃–C₈ cycloalkyl, or (C₃–C₈ cycloalkyl) C₁–C₃    alkyl, each of which may be unsubstituted or substituted with one or    more substituents selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, and    mono- or di(C₁–C₆)alkylamino.

Additional preferred compounds of the above formula II include thosecompounds of the following formula:

wherein:

-   Ar₁ is phenyl, phenylalkyl, thienyl, imidazolyl, pyridyl, pyrimidyl,    benzodioxinyl, benzodioxolyl, each of which may be optionally    substituted or substituted with up to four groups independently    selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino; Ar₂ is defined as in Claim 4;-   R₁ is hydrogen, C₁–C₇ alkyl, halogen or phenyl optionally    substituted with C₁–C₆ alkyl, C₁–C₆ alkoxy, halogen, hydroxy, amino,    or mono- or di(C₁–C₆)alkylamino;-   R₂ is C₁–C₈ alkyl or C₃–C₈ cycloalkyl; and-   R₃ is hydrogen or C₁–C₇ alkyl; and-   R₄ is phenyl, phenyl(C₁–C₄)alkyl, chromanyl, pyrrolyl, furanyl,    thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,    pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,    benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino,    mono- or di(C₁–C₆)alkylamino; or-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,        C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino.

Additional preferred compounds of the above formula II include thosecompounds of the following formula:

wherein:

-   Ar₁ is phenyl, phenylalkyl, thienyl, or pyridyl, each of which may    be optionally substituted or substituted with up to four groups    independently selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino;-   Ar₂ is defined as in formula II;-   R₁ is hydrogen, methyl, ethyl, or optionally substituted phenyl;-   R₂ is C₃–C₈ alkyl or C₃–C₈ cycloalkyl; and-   R₃ is hydrogen or methyl; and-   R₄ is C₁–C₈ alkyl, C₃–C₈ cycloalkyl, or (C₃–C₈ cycloalkyl) C₁–C₃    alkyl, each of which may be unsubstituted or substituted with one or    more substituents selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, and    mono- or di(C₁–C₆)alkylamino.

Additional preferred compounds of the above formula II include those ofthe following formula:

wherein:

-   Ar₁ is phenyl, phenylalkyl, thienyl, or pyridyl, each of which may    be optionally substituted or substituted with up to four groups    independently selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino;-   Ar₂ is defined as in Claim 4;-   R₁ is hydrogen, methyl, ethyl, or phenyl;-   R₂ is C₃–C₈ alkyl or C₃–C₈ cycloalkyl; and-   R₃ is hydrogen or methyl; and-   R₄ is phenyl, phenyl(C₁–C₄)alkyl, thienyl, pyridyl, pyrimidyl,    pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, quinazolinyl, or quinoxalinyl, each of which may be    optionally substituted or substituted with up to four groups    independently selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino; or-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,        C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino.

Still additional preferred compounds of the above formula Ii include ofthe following formula:

wherein:

-   Ar₁ is phenyl, phenylalkyl, thienyl, or pyridyl, each of which may    be optionally substituted or substituted with up to four groups    independently selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino;-   Ar₂ is chosen from phenyl, phenyl(C₁–C₄)alkyl, thienyl, pyridyl,    pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl,    benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl,    benz[d]isoxazolyl, quinolinyl, isoquinolinyl, and quinoxalinyl, each    of which may be optionally substituted or substituted with up to    four groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino,    mono- or di(C₁–C₆)alkylamino, carboxylic acid, esters of carboxylic    acids, aminocarbonyl, mono or di(C₁–C₆)alkylaminocarbonyl,    N—(C₁–C₆)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,    and 1-piperidyl; or-   Ar₂ is a bicyclic oxygen-containing groups of the formula:

-   -   wherein R_(B) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,        C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino;

-   R₁ is hydrogen, methyl, ethyl, or phenyl;

-   R₂ is C₃–C₈ alkyl or C₃–C₈cycloalkyl; and

-   R₃ is hydrogen or methyl; and

-   R₄ is C₁–C₈ alkyl, C₃–C₈ cycloalkyl, or (C₃–C₈ cycloalkyl) C₁–C₃    alkyl, each of which may be unsubstituted or substituted with one or    more substituents selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, and    mono- or di(C₁–C₆)alkylamino.

Still further preferred compounds of the above formula II include thoseof the following formula:

wherein:

-   Ar₁ is phenyl, phenyl(C₁–C₄)alkyl, thienyl, or pyridyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino,    mono- or di(C₁–C₆)alkylamino;-   Ar₂ is chosen from phenyl, phenyl(C₁–C₄)alkyl, thienyl, pyridyl,    pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl,    benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl,    benz[d]isoxazolyl, quinolinyl, isoquinolinyl, and quinoxalinyl, each    of which may be optionally substituted or substituted with up to    four groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino,    mono- or di(C₁–C₆)alkylamino, carboxylic acid, esters of carboxylic    acids, aminocarbonyl, mono or di(C₁–C₆)alkylaminocarbonyl,    N—(C₁–C₆)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,    and 1-piperidyl; or-   Ar₂ is a bicyclic oxygen-containing groups of the formula:

-   -   wherein R₈ represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,        C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino;

-   R₁ is hydrogen, methyl, ethyl, or phenyl;

-   R₂ is C₃–C₈ alkyl or C₃–C₈ cycloalkyl; and

-   R₃ is hydrogen or methyl; and

-   R₄ is phenyl, phenyl(C₁–C₄)alkyl, thienyl, pyridyl, pyrimidyl,    pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, quinazolinyl, or quinoxalinyl, each of which may be    optionally substituted or substituted with up to four groups    independently selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino; or

-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,        C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino.

Preferred compounds of the invention also include those of the followingformula III:

or a pharmaceutically acceptable salt thereof, wherein:

-   Ar₁ is phenyl, phenyl(C₁–C₄)alkyl, thienyl, or pyridyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino,    mono- or di(C₁–C₆)alkylamino;-   Ar₂ is a bicyclic oxygen-containing groups of the formula:

-   -   wherein R_(B) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,        C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino;

-   R₁ is selected from    -   i) hydrogen, halogen, hydroxy, amino, C₁–C₆ alkoxy, mono- or        di(C₁–C₆)alkylamino, cyano, nitro, haloalkyl, and    -   ii) C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl,        and (C₃–C₈)cycloalkyl) C₁–C₃ alkyl, each of which may be        unsubstituted or substituted by one or more of halogen, nitro,        cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,        acetoxy, alkoxy, amino, and mono- or di(C₁–C₆)alkylamino; or

-   R₁ is selected from    -   phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl,        thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,        triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of        which may be optionally substituted or substituted with up to        four groups independently selected from halogen, nitro, cyano,        trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,        C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino,        and mono- or di(C₁–C₆)alkylamino;

-   R₂ and R₃ are independently selected from    -   i) hydrogen, halogen, hydroxy, amino, C₁–C₆ alkoxy, mono- or        di(C₁–C₆)alkylamino, cyano, nitro, haloalkyl, and    -   ii) C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl,        and (C₃–C₈ cycloalkyl) C₁–C₃ alkyl, each of which may be        unsubstituted or substituted by one or more of halogen, nitro,        cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,        acetoxy, C₁–C₆ alkoxy, amino, mono- or di(C₁–C₆)alkylamino; and

-   R₄ is C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl,    (C₃–C₈ cycloalkyl) C₁–C₃ alkyl, each of which may be unsubstituted    or substituted with one or more substituents selected from halogen,    nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,    acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy,    amino, and mono- or di(C₁–C₆)alkylamino; or

-   R₄ is phenyl, phenyl(C₁–C₄)alkyl, chromanyl, pyrrolyl, furanyl,    thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,    pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,    benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino,    mono- or di(C₁–C₆)alkylamino, carboxylic acid, esters of carboxylic    acids, aminocarbonyl, mono or di(C₁–C₆)alkylaminocarbonyl,    N—(C₁–C₆)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,    and 1-piperidyl; or

-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,        C₁–C₆, alkoxy, amino, and mono- or di(C₁–C₆)alkylamino.

Preferred compounds of the above formula III include those wherein:

-   R₁ is hydrogen, methyl, ethyl, or phenyl;-   R₂ is C₃–C₈ alkyl or C₃–C₈ cycloalkyl;-   R₃ is hydrogen or methyl; and-   R₄ is C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl,    (C₃–C₈ cycloalkyl) C₁–C₃ alkyl, each of which may be unsubstituted    or substituted with one or more substituents selected from halogen,    nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,    acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy,    amino, and mono- or di(C₁–C₆)alkylamino.

Additional preferred compounds of formula III include those wherein:

-   R₁ is hydrogen, methyl, ethyl, or phenyl;-   R₂ is C₃–C₈ alkyl or C₃–C₈ cycloalkyl;-   R₃ is hydrogen or methyl; and-   R₄ is C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl,    (C₃–C₈ cycloalkyl) C₁–C₃ alkyl, each of which may be unsubstituted    or substituted with one or more substituents selected from halogen,    nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,    acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy,    amino, and mono- or di(C₁–C₆)alkylamino.

Still additional preferred compounds of formula III above include thosewherein:

-   R₁ is hydrogen, methyl, ethyl, or phenyl;-   R₂ is C₃–C₈ alkyl or C₃–C₈cycloalkyl;-   R₃ is hydrogen or methyl; and-   phenyl, phenyl(C₁–C₄)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl,    naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxinyl,    benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl,    quinazolinyl, or quinoxalinyl, each of which may be optionally    substituted or substituted with up to four groups independently    selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino.

Preferred compounds of formula III above also include those wherein:

-   R₁ is hydrogen, methyl, ethyl, or phenyl;-   R₂ is C₃–C₈ alkyl or C₃–C₈ cycloalkyl;-   R₃ is hydrogen or methyl; and-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,        C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino.

The invention also includes compounds of the following formula IV:

or a pharmaceutically acceptable salt thereof, wherein:

-   n is an integer from 0 to 3; and-   R₂ is hydrogen or    -   alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, or        haloalkyl, each or which may be substituted or unsubstituted;-   R₄ is hydrogen or    -   alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,        haloalkyl, each or which may be substituted or unsubstituted; or-   R₄ is optionally substituted carbocyclic aryl, optionally    substituted arylalkyl, or an optionally substituted heteroaromatic    or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in    each ring and from 1 to 3 hetero atoms,-   R₃ and R_(3A) are the same or different and represent hydrogen or    alkyl; or-   R₃ and R_(3A), taken together with the carbon atom to which they are    attached, form a cycloalkyl ring;-   R₅ and R₆ are the same or different and represent hydrogen, halogen,    hydroxy, alkyl, or alkoxy; or-   R₅ and R₆, taken together with the carbon atom to which they are    attached form a cycloalkyl ring;-   R_(5a) and R_(6a) are the same or different, and are independently    selected at each occurrence from hydrogen, halogen, hydroxy, alkyl,    and alkoxy;-   R₇ represents hydrogen or alkyl;-   Ar₁ and Ar₂ are independently optionally substituted carbocyclic    aryl, optionally substituted arylalkyl, or an optionally substituted    heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8    members in each ring and from 1 to 3 hetero atoms.

Also preferred are compounds of that formula IV above (such preferredcompounds referred to as compounds of formula IV-A) wherein n, R₃,R_(3A), R₅, R₆, R_(5a), R_(6a), and R₇ are as defined in that formulaIV, and

-   R₂ is hydrogen or-   alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, or    haloalkyl, each or which unsubstituted or substituted by one or more    of halogen, nitro, cyano, trifluormethyl, trifluoromethoxy,    haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or    dialkylamino;-   R₄ is hydrogen or    -   alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,        haloalkyl, each or which may be unsubstituted or substituted        with one or more substituents selected from halogen, nitro,        cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,        acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino and mono- or        dialkylamino, R₄ is phenyl, phenylalkyl, chromanyl, pyrrolyl,        furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl,        isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl,        tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl,        naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl,        isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,        benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,        isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each        of which may be optionally substituted or substituted with up to        four groups independently selected from halogen, nitro, cyano,        trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,        alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino,        aminoalkoxy, carboxylic acid, esters of carboxylic acids,        aminocarbonyl, mono or dialkylaminocarbonyl,        N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,        1-piperidyl and —XR_(B), wherein X and R_(B) are as defined        below; or-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and        mono- or dialkylamino;

-   Ar₁ and Ar₂ are independently chosen from

-   i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl,    pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,    pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,    benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino,    aminoalkoxy, carboxylic acid, esters of carboxylic acids,    aminocarbonyl, mono or dialkylaminocarbonyl,    N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,    1-piperidyl and —XR_(B), wherein X and R_(B) are as defined below;    and

-   ii) bicyclic oxygen-containing groups of the formula:

-   -   wherein R_(B) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and        mono- or dialkylamino;

-   X is independently selected at each occurrence from the group    consisting of —CH₂—, —CHR_(C)—, —O—, —S(O)_(m)—, —NH—, —NR_(C)—,    —C(═O)NH—, —C(═O)NR_(C)—, —S(O)_(m)NH—, —S(O)_(m)NR_(C)—, —NHC(═O)—,    —NR_(C)C(═O)—, NHS(O)_(m)—, —C(═O)NHS(O)_(m)—, and —NR_(C)S(O)_(m)—    (where m is 0, 1, or 2); and

-   R_(B) and R_(C), which may be the same or different, are    independently selected at each occurrence from the group consisting    of:    -   hydrogen, straight, branched, or cyclic alkyl groups, which may        contain one or more double or triple bonds, each of which may        unsubstituted or substituted with one or more substituent(s)        selected from:        -   oxo, hydroxy, —O(alkyl), —NH(alkyl), —N(alkyl)(alkyl),            —NHC(O) (alkyl), —N(alkyl)C(O) (alkyl), —NHS(O)_(x)(alkyl),            —S(O)_(x)(alkyl), —S(O)_(x)NH(alkyl),            —S(O)_(x)N(alkyl)(alkyl), (where x is 0, 1, or 2).

Also preferred are compounds of formula IV above wherein (such preferredcompounds referred to as compounds of formula IV-B)

-   n is defined as in formula IV above, and-   R₃ and R_(3A) are the same or different and represent hydrogen or    C₁–C₆ alkyl; or-   R₃ and R_(3A), taken together with the carbon atom to which they are    attached, form a C₃₋₈ cycloalkyl ring;-   R₅ and R₆ are the same or different and represent hydrogen, halogen,    hydroxy, C₁–C₆. alkyl, or C₁–C₆ alkoxy; or-   R₅ and R₆, taken together with the carbon atom to which they are    attached form a C₃₋₈ cycloalkyl ring;-   R_(5a) and R_(6b) are the same or different, and are independently    selected at each occurrence from hydrogen, halogen, hydroxy, C₁–C₆    alkyl, and C₁–C₆ alkoxy;-   R₂ is hydrogen or-   C₁–C₈ alkyl C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, (C₃₋₈    cycloalkyl) C₁₋₃ alkyl, or C₁–C₆ haloalkyl each or which    unsubstituted or substituted by one or more of halogen, nitro,    cyano, trifluormethyl, trifluoromethoxy, C₁₋₃ haloalkyl, hydroxy,    acetoxy, alkoxy, amino, and mono- or di(C₁–C₆)alkylamino;-   R₄ is hydrogen or    -   C₁₋₃ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈cycloalkyl, (C₃₋₈        cycloalkyl)C₁₋₄alkyl, haloalkyl, each or which may be        unsubstituted or substituted with one or more substituents        selected from halogen, nitro, cyano, trifluoromethyl,        trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino and mono- or        di(C₁–C₆)alkylamino,-   R₄ is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl,    pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,    pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, iscindolyl,    benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl quinolinyl,    isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono-    or di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters    of carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆,alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, —XR_(B), wherein X and    R_(B) are as defined below; or-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆        alkoxy, amino, and mono- or di(C₁–C₆)alkylamino;

-   Ar₁ and Ar₂ are independently chosen from

-   i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl,    pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,    pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,    benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono-    or di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters    of carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and —XR_(B), wherein X    and R_(B) are as defined below; and

-   ii) bicyclic oxygen-containing groups of the formula:

-   -   wherein R_(B) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆        alkoxy, amino, and mono- or di(C₁–C₆)alkylamino;

-   X is independently selected at each occurrence from the group    consisting of —CH₂—, —CHR_(C)—, —O—, —S(O)_(m)—, —NH—, —NR_(C)—,    —C(═O)NH—, —C(═O)NR_(C)—, S(O)_(m)NH—, —S(O)_(m)NR_(C)—, —NHC(═O)—,    —NR_(C)C(═O)—, —NHS(O)_(m)—, —C(═O)NHS(O)_(m)—, and —NR_(C)S(O)_(m)—    (where m is 0, 1, or 2); and

-   R_(B) and R_(C), which may be the same or different, are    independently selected at each occurrence from the group consisting    of:    -   hydrogen, straight, branched, or cyclic alkyl groups, which may        contain one or more double or triple bonds, each of which may        unsubstituted or substituted with one or more substituent(s)        selected from:        -   oxo, hydroxy, —O(C₁–C₆ alkyl), —NH(C₁–C₆ alkyl), —N(C₁–C₆            alkyl)(C₁–C₆ alkyl), —NHC(O)(C₁–C₆ alkyl), —N(C₁–C₆            alkyl)C(O)(C₁₋₆ alkyl), —NHS(O)_(x)(C₁–C₆ alkyl),            —S(O)_(x)(C₁–C₆ alkyl), —S(O)_(x)NH(C₁–C₆ alkyl),            —S(O)_(x)N(C₁–C₆ alkyl)(C₁–C₆ alkyl), (where x is 0, 1, or            2).

Also preferred are compounds of formula IV above (such preferredreferred to as compounds of formula IV-C) wherein n, R₂, R₃, R_(3A), R₅,R₆, R_(5a), R_(6a), and R₇ are as defined in formula IV above,

-   R₄ is hydrogen or    -   C₁–C₈ alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl, C₃–C₈cycloalkyl,        (C₃–C₈cycloalkyl) C₁–C₄alkyl, haloalkyl, each or which may be        unsubstituted or substituted with one or more substituents        selected from halogen, nitro, cyano, trifluoromethyl,        trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl,        C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino and mono- or        di(C₁–C₆)alkylamino,-   R₄ is phenyl, naphthyl, thienyl, pyridyl, pyrimidyl,    dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which    may be optionally substituted or substituted with up to four groups    independently selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters of    carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, —XR_(B), wherein X and    R_(a) are as defined below; or-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,        C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino;

-   Ar₁ is phenyl, thienyl, or pyridyl, pyrimidyl, dihydrobenzofuranyl,    furanyl, benzodioxanyl, indolyl, each of which is unsubstituted or    substituted with up to four substituents independently selected    from:    -   halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,        haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆        alkynyl, C₁–C₆ alkoxy, amino, mono- or di(C₁–C₆)alkylamino,        amino(C₁–C₆)alkoxy, carboxylic acid, esters of carboxylic acids,        aminocarbonyl, mono or di(C₁–C₆)alkylaminocarbonyl,        N—(C₁–C₆)alkylsulfonylaminocarbonyl, 1-azetidinyl,        1-pyrrolidinyl, 1-piperidyl, and —XR_(B), wherein X and R_(B)        are as defined below;

-   Ar₂ is phenyl, naphthyl, thienyl, pyridyl, pyrimidyl,    dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which    may be optionally substituted or substituted with up to four groups    independently selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters of    carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁-occurrence from hydrogen and    methyl.

Further preferred are compounds of the above formula IV-C wherein:

-   R₃ and R₄ are hydrogen;-   R₅ and R₆ are the same or different and represent hydrogen or    methyl; and-   R_(5a) and R_(6a) are the same or different, and are independently    selected at each occurrence from hydrogen and methyl.

Further preferred are compounds of the above formula IV-C wherein:

or a pharmaceutically acceptable salt thereof, wherein:

-   n is an integer from 0 to 3; and-   R₂ is hydrogen or    -   alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, or        haloalkyl, each or which may be substituted or unsubstituted;-   R₄ is hydrogen or    -   C₁–C₈ alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl, C₃–C₈cycloalkyl,        (C₃–C₈cycloalkyl) C₁–C₄alkyl, haloalkyl, each or which may be        unsubstituted or substituted with one or more substituents        selected from halogen, nitro, cyano, trifluoromethyl,        trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl,        C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino and mono- or        di(C₁–C₆)alkylamino,-   R₄ is phenyl, naphthyl, thienyl, pyridyl, pyrimidyl,    dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which    may be optionally substituted or substituted with up to four groups    independently selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters of    carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, —XR_(B), wherein X and    R_(B) are as defined below; or-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,        C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino;

-   Ar₂ is phenyl, naphthyl, thienyl, pyridyl, pyrimidyl,    dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which    may be optionally substituted or substituted with up to four groups    independently selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters of    carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and —XR_(B), wherein X    and R_(B) are as defined below; or

-   Ar₂ is a bicyclic oxygen-containing group of the formula:

-    C₆)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,    1-piperidyl, and —XR_(B), wherein X and R_(B) are as defined below;    or-   Ar₂ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A)′ represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,        C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino;

-   X is independently selected at each occurrence from the group    consisting of —CH₂—, —CHR_(C)—, —O—, —S(O)_(m)—, —NH—, —NR_(C)—,    —C(═O)NH—, —C(═O)NR_(C)—, —S(O)_(m)NH—, —S(O)_(m)NR_(C)—, —NHC(═O)—,    —NR_(C)C(═O)—, —NHS(O)_(m)—, —C(═O)NHS(O)_(m)—, and —NR_(C)S(O)_(m)—    (where m is 0, 1, or 2); and

-   R_(B) and R_(C), which may be the same or different, are    independently selected at each occurrence from the group consisting    of:    -   hydrogen, straight, branched, or cyclic alkyl groups, which may        contain one or more double or triple bonds, each of which may        unsubstituted or substituted with one or more substituent(s)        selected from:        -   oxo, hydroxy, —O(C₁–C₆ alkyl), —NH(C₁–C₆ alkyl), —N(C₁–C₆            alkyl)(C₁–C₆ alkyl), —NHC(O)(C₁–C₆ alkyl), —N(C₁–C₆            alkyl)C(O)(C₁–C₆ alkyl), —NHS(O)_(x)(C₁–C₆ alkyl),            —S(O)_(x)(C₁–C₆ alkyl), —S(O)_(m)NH(C₁–C₆ alkyl),            —S(O)_(m)N(C₁–C₆ alkyl)(C₁–C₆ alkyl), (where x is 0, 1, or            2).

Further preferred are compounds of the above formula IV-C wherein:

-   R₃ and R₄ are the same or different and represent hydrogen or    methyl;-   R₅ and R₆ are the same or different and represent hydrogen or    methyl; and-   R_(5a) and R_(6a) are the same or different, and are independently    selected at each wherein R_(A)′ represents 0 to 3 groups selected    from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,    haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆    alkynyl, C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino;-   X is independently selected at each occurrence from the group    consisting of —CH₂—, —CHR_(C)—, —O—, —S(O)_(m)—, —NH—, —NR_(C)—,    —C(═O)NH—, —C(═O)NR_(C)—, —S(O)_(m)NH—, S(O)_(m)NR_(C)—, —NHC(═O)—,    —NR_(C)C(═O)—, —NHS(O)_(m)—, —C(═O)NHS(O)_(m)—, and —NR_(C)S(O)_(m)—    (where m is 0, 1, or 2); and-   R_(B) and R_(C), which may be the same or different, are    independently selected at each occurrence from the group consisting    of:    -   hydrogen, straight, branched, or cyclic alkyl groups, which may        contain one or more double or triple bonds, each of which may        unsubstituted or substituted with one or more substituent(s)        selected from:        -   oxo, hydroxy, —O(C₁–C₆ alkyl), —NH(C₁–C₆ alkyl), —N(C₁–C₆            alkyl)(C₁–C₆ alkyl), —NHC(O)(C₁–C₆ alkyl), —N(C₁–C₆            alkyl)C(O)(C₁–C₆ alkyl), —NHS(O)_(x)(C₁–C₆ alkyl),            —S(O)_(x)(C₁–C₆ alkyl), —S(O)_(m)NH(C₁–C₆ alkyl),            —S(O)_(m)N(C₁–C₆ alkyl)(C₁–C₆ alkyl), (where x is 0, 1, or            2).-   R₅ and R₆ are the same or different and represent hydrogen or    methyl;-   R_(5a) and R_(6a) are the same or different, and are independently    chosen at each occurrence from hydrogen and methyl; and-   R_(X) represents up to four substituents independently chosen from    hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,    haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆    alkynyl, C₁–C₆ alkoxy, amino, mono- or di(C₁–C₆)alkylamino, and    amino(C₁–C₆)alkoxy.

Further preferred are compounds of the above formula IV-C wherein:

or a pharmaceutically acceptable salt thereof, wherein:

-   n is an integer from 0 to 3; and-   R₄ is hydrogen or    -   C₁–C₈ alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl, C₃–C₈cycloalkyl,        (C₃–C₈cycloalkyl) C₁–C₄alkyl, haloalkyl, each or which may be        unsubstituted or substituted with one or more substituents        selected from halogen, nitro, cyano, trifluoromethyl,        trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl,        C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino and mono- or        di(C₁–C₆)alkylamino,-   R₄ is phenyl, naphthyl, thienyl, pyridyl, pyrimidyl,    dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which    may be optionally substituted or substituted with up to four groups    independently selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters of    carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, —XR_(B), wherein X and    R_(B) are as defined below; or-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,        C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino;

-   Ar₂ is phenyl, naphthyl, thienyl, pyridyl, pyrimidyl,    dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which    may be optionally substituted or substituted with up to four groups    independently selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters of    carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and —XR_(B), wherein X    and R_(B) are as defined below; or

-   Ar₂ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A)′ represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,        C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino;

-   X is independently selected at each occurrence from the group    consisting of —CH₂—, —CHR_(C)—, —O—, —S(O)_(m)—, —NH—, —NR_(C)—,    —C(═O)NH—, —C(═O)NR_(C)—, —S(O)_(m)NH—, —S(O)_(m)NR_(C)—, —NHC(═O)—,    —NR_(C)C(═O)—, —NHS(O)_(m)—, —C(═O)NHS(O)_(m)—, and —NR_(C)S(O)_(m)—    (where m is 0, 1, or 2); and

-   R_(B) and R_(C), which may be the same or different, are    independently selected at each occurrence from the group consisting    of:    -   hydrogen, straight, branched, or cyclic alkyl groups, which may        contain one or more double or triple bonds, each of which may        unsubstituted or substituted with one or more substituent(s)        selected from:        -   oxo, hydroxy, —O(C₁–C₆ alkyl), —NH(C₁–C₆ alkyl), —N(C₁–C₆            alkyl)(C₁–C₆ alkyl), —NHC(O)(C₁–C₆ alkyl), —N(C₁–C₆            alkyl)C(O)(C₁–C₆ alkyl), —NHS(O)_(x)(C₁–C₆ alkyl),            —S(O)_(x)(C₁–C₆ alkyl), —S(O)_(x)NH(C₁–C₆ alkyl),            —S(O)_(m)N(C₁–C₆ alkyl)(C₁–C₆ alkyl), (where x is 0, 1, or            2).

-   R₂ is C₃–C₈ straight or branched chain alkyl, C₂–C₈ alkenyl, or    C₂–C₈ alkynyl;

-   R₅ and R₆ are the same or different and represent hydrogen or    methyl;

-   R_(5a) and R_(6a) are the same or different, and are independently    chosen at each occurrence from hydrogen and methyl; and

-   R_(X) represents up to four substituents independently chosen from    hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,    haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₈ alkenyl, C₂–C₈    alkynyl, C₁–C₆ alkoxy, amino, mono- or di(C₁–C₆)alkylamino, and    amino(C₁–C₆)alkoxy.

Further preferred are compounds of the above formula IV-C wherein:

Ar₂, R_(X), and n are as defined in formula IV-C,

or a pharmaceutically acceptable salt thereof, wherein:

-   R₂ is C₃–C₈ straight or branched chain alkyl, C₂–C₈ alkenyl, or    C₂–C₈ alkynyl; and-   R₄ is C₁–C₈ straight or branched chain alkyl, C₂–C₈ alkenyl, or    C₂–C₈ alkynyl.

Further preferred are compounds of the above formula IV-C,

or a pharmaceutically acceptable salt thereof, wherein:

-   R₂ is C₃–C₈ straight or branched chain alkyl, C₂–C₈ alkenyl, or    C₂–C₈ alkynyl;-   R₄ is phenyl, which may be unsubstituted or substituted with:    -   C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl,        (C₃–C₈ cycloalkyl)C₁–C₄ alkyl, haloalkyl, C₁–C₆ alkoxy, halogen,        hydroxy, amino, or mono- or di(C₁–C₆)alkylamino; or-   R₄ is a bicyclic oxygen containing group of the formula:

-   wherein R_(A) is hydrogen, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆    alkynyl, C₃–C₈ cycloalkyl, (C₃–C₈cycloalkyl) C₁–C₄ alkyl, haloalkyl,    alkoxy, halogen, hydroxy, amino, or mono- or di(C₁–C₆)alkylamino;-   Ar₂ is phenyl which is unsubstituted or optionally substituted or    substituted with up to four groups independently selected from:    -   halogen, C₁–C₇ alkyl, C₁–C₇ alkoxy, cyano, amino, mono- or        di(C₁–C₆)alkylamino, carboxylic acid, esters of carboxylic        acids, aminocarbonyl, mono or dialkylaminocarbonyl,        N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,        1-piperidyl, 1-morpholino, nitro, hydroxy, acetoxy,        trifluoromethyl, and trifluoromethoxy or —XR_(B), wherein X and        R_(B) are as defined for formula IV-C; or-   Ar₂ is a bicyclic oxygen-containing group of the formula:

wherein R_(A), R_(A)′, and n are as defined in formula IV-C.

Also preferred are compounds of formula IV-C as specified above,wherein:

-   n is an integer from 0 to 3;-   R₂ is C₃–C₈ straight or branched chain alkyl, C₂–C₈ alkenyl, or    C₂–C₈ alkynyl;-   R₄ is C₁–C₈ straight or branched chain alkyl, C₂–C₈ alkenyl, or    C₂–C₈ alkynyl;-   Ar₂ is a bicyclic oxygen containing group of the formula:

-   wherein R_(A)′ represents 0 to 3 groups selected from halogen,    nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,    acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy,    amino, and mono- or di(C₁–C₆)alkylamino.

Additional preferred compounds include those of the following formula V:

wherein:

-   n is an integer from 0 to 3;-   R₃ and R_(3A) are the same or different and represent hydrogen,    halogen, hydroxy, alkyl, or alkoxy; or-   R₃ and R_(3A), taken together with the carbon atom to which they are    attached, form a cycloalkyl ring;-   R₅ and R₆ are the same or different and represent hydrogen, halogen,    hydroxy, alkyl, or alkoxy; or-   R₅ and R₆, taken together with the carbon atom to which they are    attached form a cycloalkyl ring; and-   R_(5A) and R_(6A) are the same or different and represent hydrogen,    halogen, hydroxy, alkyl, or alkoxy.

Preferred compounds of formula V include those compounds wherein:

-   R₃ and R_(3A) are the same or different and represent hydrogen or    C₁–C₆ alkyl; or-   R₃ and R_(3A), taken together with the carbon atom to which they are    attached, form a cycloalkyl ring of from three to six carbon atoms;-   R₅ and R₆ are the same or different and represent hydrogen, halogen,    hydroxy, C₁–C₆ alkyl, or C₁–C₆ alkoxy; or-   R₅ and R₆, taken together with the carbon atom to which they are    attached form a cycloalkyl ring of from three to six carbon atoms;    and-   R_(5A) and R_(6A) are the same or different and represent hydrogen,    halogen, hydroxy, C₁–C₆ alkyl, or C₁–C₆ alkoxy.

Preferred compounds of formula V include those compounds wherein:

R₃ and R₄ are hydrogen; and

R₅, R₆, R_(5A), and R_(6A) are the same or different and representhydrogen or methyl.

The invention also includes compounds of the following formula VI:

wherein:

-   n is an integer from 0 to 3;-   R₂ is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, or    haloalkyl, each of which may be substituted or unsubstituted;-   R₃ and R₄ are the same or different and represent hydrogen or alkyl;    or-   R₃ and R_(3a), taken together with the carbon atom to which they are    attached, form a cycloalkyl ring;-   R₅ and R₆ are the same or different and represent hydrogen, halogen,    hydroxy, alkyl, or alkoxy; or-   R₅ and R₆, taken together with the carbon atom to which they are    attached, form a cycloalkyl ring;-   R_(5A) and R_(6A) are the same or different and represent hydrogen,    halogen, hydroxy, alkyl, or alkoxy; and-   Ar₁ is unsubstituted or substituted carbocyclic aryl, unsubstituted    or substituted arylalkyl, or a unsubstituted or substituted    heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3    to 8 members in each ring and from 1 to 3 hetero atoms.

Preferred compounds of formula VI include those compounds wherein:

-   R₂ is C₁–C₈ straight or branched chain alkyl, C₂–C₈ alkenyl, C₂–C₈    alkynyl, C₃–C₈ cycloalkyl, C₂–C₈ (cycloalkyl)C₁–C₄ alkyl, or C₁–C₈    haloalkyl;-   R₃ and R_(3a) are the same or different and represent hydrogen or    C₁–C₆ alkyl; or-   R₃ and R_(3a), taken together with the carbon atom to which they are    attached, form a cycloalkyl ring of from three to six carbon atoms;    and-   R₅ and R₆ are the same or different and represent hydrogen, halogen,    hydroxy, C₁–C₆ alkyl, or C₁–C₆ alkoxy; or-   R₅ and R₆, taken together with the carbon atom to which they are    attached form a cycloalkyl ring of from three to six carbon atoms;-   R_(5A) and R_(6A) are the same or different and represent hydrogen,    halogen, hydroxy, C₁–C₆ alkyl, or C₁–C₆ alkoxy;-   Ar₁ is phenyl, thienyl, or pyridyl, pyrimidyl, dihydrobenzofuranyl,    furanyl, benzodioxanyl, indolyl, each of which is unsubstituted or    substituted with up to four substituents independently selected    from:    -   halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,        haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆        alkynyl, C₁–C₆ alkoxy, amino, mono- or di(C₁–C₆)alkylamino,        amino(C₁–C₆)alkoxy, carboxylic acid, esters of carboxylic acids,        aminocarbonyl, mono or di(C₁–C₆)alkylaminocarbonyl,        N—(C₁–C₆)alkylsulfonylaminocarbonyl, 1-azetidinyl,        1-pyrrolidinyl, 1-piperidyl, and —XR_(B), wherein X and R_(B)        are as defined below;-   X is independently selected at each occurrence from the group    consisting of —CH₂—, —CHR_(C)—, —O—, —S(O)_(m)—, —NH—, —NR_(C)—,    —C(═O)NH—, —C(═O)NR_(C)—, —S(O)_(m)NH—, —S(O)_(m)NR_(C)—, —NHC(═O)—,    —NR_(C)C(═O)—, —NHS(O)_(m)—, —C(═O)NHS(O)_(m)—, and —NR_(C)S(O)_(m)—    (where m is 0, 1, or 2); and-   R_(B) and R_(C), which may be the same or different, are    independently selected at each occurrence from the group consisting    of:    -   hydrogen, straight, branched, or cyclic alkyl groups, which may        contain one or more double or triple bonds, each of which may        unsubstituted or substituted with one or more substituent(s)        selected from:        -   oxo, hydroxy, —O(C₁–C₆ alkyl), —NH(C₁–C₆ alkyl), —N(C₁–C₆            alkyl)(C₁–C₆ alkyl), —NHC(O)(C₁–C₆ alkyl), —N(C₁–C₆            alkyl)C(O)(C₁–C₆ alkyl), —NHS(O)_(x)(C₁–C₆ alkyl),            —S(O)_(x)(C₁–C₆ alkyl), —S(O)_(x)NH(C₁–C₆ alkyl),            —S(O)_(x)N(C₁–C₆ alkyl)(C₁–C₆ alkyl), (where x is 0, 1, or            2).

Preferred compounds of the above formula VI include those of thefollowing formula:

wherein:

-   n is 0, 1, or 2:-   R₂ is C₃–C₈ straight or branched chain alkyl, C₂–C₈ alkenyl, or    C₂–C₈ alkynyl;-   R₅, R₆, R_(5A), and R_(6A) are the same or different and represent    hydrogen or methyl; and-   R_(X) represents up to four substituents independently chosen from    hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,    haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₈ alkenyl, C₂–C₈    alkynyl, C₁–C₆ alkoxy, amino, mono- or di(C₁–C₆)alkylamino, and    amino(C₁–C₆)alkoxy.

The invention also includes compounds of the following formula VII:

wherein:

-   n is an integer from 0 to 3; and-   R₂ is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,    haloalkyl, each or which may be substituted or unsubstituted;-   R₃ and R_(3A) are the same or different and represent hydrogen or    alkyl; or-   R₃ and R_(3a), taken together with the carbon atom to which they are    attached, form a cycloalkyl ring;-   R₅ and R₆ are the same or different and represent hydrogen or alkyl;    or-   R₅ and R₆, taken together with the carbon atom to which they are    attached, form a cycloalkyl ring;-   R_(5a) and R_(6a) are the same or different, and are independently    selected at each occurrence from hydrogen, halogen, hydroxy, alkyl,    and alkoxy;-   R₇ represents hydrogen or alkyl; and    Ar₁ is optionally substituted carbocyclic aryl, optionally    substituted arylalkyl, or an optionally substituted heteroaryl or    heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in    each ring and from 1 to 3 hetero atoms.

Preferred compounds of formula VII include those of the followingformula:

wherein:

-   n is an integer from 0 to 3;-   R₂ is C₃–C₈ straight or branched chain alkyl, C₂–C₈ alkenyl, or    C₂–C₈ alkynyl;-   R₅, R₆, R_(5A), and R_(6A) are the same or different and represent    hydrogen or methyl; and-   R_(X) represents up to four substituents independently chosen from    hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,    haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₈ alkenyl, C₂–C₈    alkynyl, C₁–C₆ alkoxy, amino, mono- or di(C₁–C₆)alkylamino, and    amino(C₁–C₆)alkoxy.

The invention also includes methods of synthesis of compounds of theinvention. In particular, the invention includes methods to synthesiscompounds of the following formula VIII:

wherein:

-   n is an integer from 0 to 3; and-   R₂ is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl,    (cycloalkyl)alkyl, or haloalkyl, each or which may be substituted or    unsubstituted;-   R₄ is hydrogen or    -   alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,        haloalkyl, each or which may be substituted or unsubstituted; or-   R₄ is optionally substituted carbocyclic aryl, optionally    substituted arylalkyl, or an optionally substituted heteroaromatic    or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in    each ring and from 1 to 3 hetero atoms,-   R₃ and R_(3A) are the same or different and represent hydrogen or    alkyl; or-   R₃ and R_(3A), taken together with the carbon atom to which they are    attached, form a cycloalkyl ring;-   R₅ and R₆ are the same or different and represent hydrogen, halogen,    hydroxy, alkyl, or alkoxy; or-   R₅ and R₆, taken together with the carbon atom to which they are    attached form a cycloalkyl ring;-   R_(5a) and R_(6a) are the same or different, and are independently    selected at each occurrence from hydrogen, halogen, hydroxy, alkyl,    and alkoxy;-   R₇ represents hydrogen or alkyl;-   Ar₁ and Ar₂ are independently optionally substituted carbocyclic    aryl, optionally substituted arylalkyl, or an optionally substituted    heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8    members in each ring and from 1 to 3 hetero atoms. the process    comprising:    reacting a compound of the formula:

wherein Y is halogen or sulfonate ester,in a suitable solvent in the presence of a suitable base,with a secondary amine of the formula:

In that synthetic method, preferred are compounds (referred to ascompounds of formula VIII-A) wherein

-   n and Y are as defined above for formula VIII;-   R₃ and R_(3A) are the same or different and represent hydrogen or-   C₁–C₆ alkyl; or-   R₃ and R_(3A), taken together with the carbon atom to which they are    attached, form a C₃₋₈ cycloalkyl ring;-   R₅ and R₆ are the same or different and represent hydrogen, halogen,    hydroxy, C₁–C₆ alkyl, or C₁–C₆ alkoxy; or-   R₅ and R₆, taken together with the carbon atom to which they are    attached form a C₃₋₈ cycloalkyl ring;-   R_(5a) and R_(6a) are the same or different, and are independently    selected at each occurrence from hydrogen, halogen, hydroxy, C₁–C₆    alkyl, and C₁–C₆ alkoxy;-   R₂ is hydrogen or-   C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, (C₃₋₈    cycloalkyl) C₁₋₃ alkyl, or C₁–C₆ haloalkyl, each or which    unsubstituted or substituted by one or more of halogen, nitro,    cyano, trifluormethyl, trifluoromethoxy, C₁₋₃ haloalkyl, hydroxy,    acetoxy, alkoxy, amino, and mono- or di(C₁–C₆)alkylamino;-   R₄ is hydrogen or    -   C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈cycloalkyl, (C₃₋₈        cycloalkyl)C₁₋₄alkyl, haloalkyl, each or which may be        unsubstituted or substituted with one or more substituents        selected from halogen, nitro, cyano, trifluoromethyl,        trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino and mono- or        di(C₁–C₆)alkylamino,-   R₄ is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl,    pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,    pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,    benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono-    or di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters    of carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, —XR_(B), wherein X and    R_(B) are as defined below; or-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆        alkoxy, amino, and mono- or di(C₁–C₆)alkylamino;

-   Ar₁ and Ar₂ are independently chosen from

-   i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl,    pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,    pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,    benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C:—C₆ alkoxy, amino, mono-    or di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters    of carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and —XR_(B), wherein X    and R_(B) are as defined below; and

-   ii) bicyclic oxygen-containing groups of the formula:

-   -   wherein R_(B) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆        alkoxy, amino, and mono- or di(C₁–C₆)alkylamino:

-   X is independently selected at each occurrence from the group    consisting of —CH₂—, —CHR_(C)—, —O—, —S(O)_(m)—, —NH—, —NR_(C)—,    —C(═O)NH—, —C(═O)NR_(C)—, S(O)_(m)NH—, S(O)_(m)NR_(C)—, —NHC(═O)—,    —NR_(C)C(═O)—, —NHS(O)_(m)—, —C(═O)NHS(O)_(m)—, and —NR_(C)S(O)_(m)—    (where m is 0, 1, or 2); and

-   R_(B) and R_(C), which may be the same or different, are    independently selected at each occurrence from the group consisting    of:    -   hydrogen, straight, branched, or cyclic alkyl groups, which may        contain one or more double or triple bonds, each of which may        unsubstituted or substituted with one or more substituent(s)        selected from:        -   oxo, hydroxy, —O(C₁–C₆ alkyl), —NH(C₁–C₆ alkyl), —N(C₁–C₆            alkyl)(C₁–C₆ alkyl), —NHC(O)(C₁–C₆ alkyl), —N(C₁–C₆            alkyl)C(O)(C₁₋₆ alkyl), —NHS(O)_(x)(C₁–C₆ alkyl),            —S(O)_(x)(C₁–C₆ alkyl), —S(O)_(x)NH(C₁–C₆ alkyl),            —S(O)_(x)N(C₁–C₆ alkyl)(C₁–C₆ alkyl), (where x is 0, 1, or            2).

The invention also includes compounds of the above formula VIII andVIII-A, and pharmaceutically acceptable salts of such compounds.

The invention also provides compounds of the following formula IX:

or a pharmaceutically acceptable salt thereof, wherein:

-   m is 0, 1, or 2;-   R is hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl,    alkoxy, mono- or dialkylamino, optionally substituted alkyl,    optionally substituted alkenyl, optionally substituted alkynyl,    optionally substituted cycloalkyl, optionally substituted    (cycloalkyl)alkyl; or-   R is optionally substituted carbocyclic aryl, optionally substituted    arylalkyl, optionally substituted heteroaryl or heteroalicyclic    group having from 1 to 3 rings, 3 to 8 members in each ring and from    1 to 3 heteroatoms;-   R₁, R₂, R₃, R_(3A), R₅, and R₆ are independently selected from    hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy,    mono- or dialkylamino, optionally substituted alkyl, optionally    substituted alkenyl, optionally substituted alkynyl, optionally    substituted cycloalkyl, and optionally substituted    (cycloalkyl)alkyl;-   R₄ is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of    which may be optionally substituted; or-   R₄ is optionally substituted carbocyclic aryl, optionally    substituted arylalkyl, optionally substituted heteroaryl or    heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in    each ring and from 1 to 3 heteroatoms; and-   Ar₁ and Ar₂ are independently optionally substituted carbocyclic    aryl, optionally substituted arylalkyl, optionally substituted    heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8    members in each ring and from 1 to 3 heteroatoms.

Preferred compounds of formula IX include those of the following formulaIX-A:

wherein Ar₁, Ar₂, R, R₁, R₂, R₃, and R₄ are for formula IX above.

Preferred compounds of formula IX-A above include those wherein:

-   R is selected from    -   i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or        dialkylamino, cyano, nitro, haloalkyl, and    -   ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl,        each of which may be unsubstituted or substituted by one or more        of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,        haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or        dialkylamino; or-   R is selected from-   phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl,    thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,    triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which    may be optionally substituted or substituted with up to four groups    independently selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl,    alkynyl, alkoxy, amino, and mono- or dialkylamino; and-   R₁, R₂, and R₃ are independently selected from    -   i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or        dialkylamino, cyano, nitro, haloalkyl, and    -   ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl,        each of which may be unsubstituted or substituted by one or more        of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,        haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or        dialkylamino;-   R₄ is hydrogen or    -   alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,        haloalkyl, each or which may be unsubstituted or substituted        with one or more substituents selected from halogen, nitro,        cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,        acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino and mono- or        dialkylamino,-   R₄ is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl,    pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,    pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,    benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino,    aminoalkoxy, carboxylic acid, esters of carboxylic acids,    aminocarbonyl, mono or dialkylaminocarbonyl,    N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,    1-piperidyl, —XR_(B), wherein X and R_(B) are as defined below; or-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and        mono- or dialkylamino;

-   Ar₁ and Ar₂ are independently chosen from

-   i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl,    pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,    pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,    benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino,    aminoalkoxy, carboxylic acid, esters of carboxylic acids,    aminocarbonyl, mono or dialkylaminocarbonyl,    N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,    1-piperidyl, and —XR_(B), wherein X and R_(B) are as defined below;    and

-   ii) bicyclic oxygen-containing groups of the formula:

-   -   wherein R_(B) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and        mono- or dialkylamino;

-   X is independently selected at each occurrence from the group    consisting of —CH₂—, —CHR_(C)—, —O—, —S(O)_(m)—, —NH—, —NR_(C)—,    —C(═O)NH—, —C(═O)NR_(C)—, —S(O)_(m)NH—, S(O)_(m)NR_(C)—, —NHC(═O)—,    —NR_(C)C(═O)—, —NHS(O)_(m)—, —C(═O)NHS(O)_(m)—, and —NR_(C)S(O)_(m)—    (where m is 0, 1, or 2); and

-   R_(B) and R_(C), which may be the same or different, are    independently selected at each occurrence from the group consisting    of:    -   hydrogen, straight, branched, or cyclic alkyl groups, which may        contain one or more double or triple bonds, each of which may        unsubstituted or substituted with one or more substituent(s)        selected from:        -   oxo, hydroxy, —O(alkyl), —NH(alkyl), —N(alkyl)(alkyl),            —NHC(O)(alkyl), —N(alkyl)C(O)(alkyl), —NHS(O)_(x)(C₁–C₆            alkyl), —S(O)_(x)(alkyl), —S(O)_(x)NH(alkyl),            —S(O)_(x)N(alkyl)(alkyl), (where x is 0, 1, or 2).

Additional preferred compounds of formula IX-A include those wherein:R₁, R₂, and R₃ are independently selected from

-   -   i) hydrogen, halogen, hydroxy, amino, C₁–C₆ alkoxy, mono- or        di(C₁–C₆)alkylamino, cyano, nitro, haloalkyl, and    -   ii) C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl,        and (C₃–C₈ cycloalkyl) C₁–C₃ alkyl, each of which may be        unsubstituted or substituted by one or more of halogen, nitro,        cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,        acetoxy, C₁–C₆ alkoxy, amino, mono- or di(C₁–C₆)alkylamino;

-   R is selected from    -   i) hydrogen, halogen, hydroxy, amino, C₁–C₆ alkoxy, mono- or        di(C₁–C₆)alkylamino, cyano, nitro, haloalkyl, and    -   ii) C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl,        and (C₃–C₈)cycloalkyl) C₁–C₃ alkyl, each of which may be        unsubstituted or substituted by one or more of halogen, nitro,        cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,        acetoxy, alkoxy, amino, and mono- or di(C₁–C₆)alkylamino; or

-   R is selected from    -   phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl,        thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,        triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of        which may be optionally substituted or substituted with up to        four groups independently selected from halogen, nitro, cyano,        trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,        C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino,        and mono- or di(C₁–C₆)alkylamino;

-   R₄ is hydrogen or    -   C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈cycloalkyl, (C₃₋₈        cycloalkyl)C₁₋₄alkyl, haloalkyl, each or which may be        unsubstituted or substituted with one or more substituents        selected from halogen, nitro, cyano, trifluoromethyl,        trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino and mono- or        di(C₁–C₆)alkylamino,

-   R₄ is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl,    pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,    pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,    benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono-    or di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters    of carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, —XR_(B), wherein X and    R_(B) are as defined below; or

-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆        alkoxy, amino, and mono- or di(C₁–C₆)alkylamino; and

-   Ar₁ and Ar₂ are independently chosen from

-   i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl,    pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,    pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,    benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono-    or di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters    of carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and —XR_(B), wherein X    and R_(B) are as defined below; and

-   ii) bicyclic oxygen-containing groups of the formula:

-   -   wherein R_(B) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆        alkoxy, amino, and mono- or di(C₁–C₆)alkylamino;

-   X is independently selected at each occurrence from the group    consisting of —CH₂—, —CHR_(C)—, —O—, —S(O)_(m)—, —NH—, —NR_(C)—,    —C(═O)NH—, —C(═O)NR_(C)—, —S(O)_(m)NH—, —S(O)_(m)NR_(C)—, —NHC(═O)—,    —NR_(C)C(═O)—, —NHS(O)_(m)—, —C(═O)NHS(O)_(m)—, and —NR_(C)S(O)_(m)—    (where m is 0, 1, or 2); and

-   R_(B) and R_(C), which may be the same or different, are    independently selected at each occurrence from the group consisting    of:    -   hydrogen, straight, branched, or cyclic alkyl groups, which may        contain one or more double or triple bonds, each of which may        unsubstituted or substituted with one or more substituent(s)        selected from:        -   oxo, hydroxy, —O(C₁–C₆ alkyl), —NH(C₁–C₆ alkyl), —N(C₁–C₆            alkyl)(C₁–C₆ alkyl), —NHC(O)(C₁–C₆ alkyl), —N(C₁–C₆            alkyl)C(O)(C₁₋₆ alkyl), —NHS(O)_(x)(C₁–C₆ alkyl),            —S(O)_(x)(C₁–C₆ alkyl), —S(O)_(x)NH(C₁–C₆ alkyl),            —S(O)_(x)N(C₁–C₆ alkyl)(C₁–C₆ alkyl), (where x is 0, 1, or            2).

Additional preferred compounds of formula IX-A above include thosewherein:

-   R is hydrogen, halogen, C₁–C₈ alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl,    C₁–C₈ cycloalkyl, (C₃–C₈cycloalkyl)C₁–C₃ alkyl, C₁–C₈ alkoxy, or    C₁–C₈ haloalkyl, or-   R is a phenyl which may be substituted by up to five substituents    independently chosen from C₁–C₈ alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl,    C₁–C₈ alkoxy, halogen, cyano, carboxylic acid, hydroxy, acetoxy,    nitro, amino, mono or di(C₁–C₆)alkylamino, aminocarbonyl,    sulfonamido, mono or di(C₁–C₆)alkylsulfonamido, 3,4-methylenedioxy,    3,4-(1,2-ethylene)dioxy, trifluoromethyl or trifluoromethoxy;-   R₁ is hydrogen, C₁–C₈ alkyl, C₂–C₈alkenyl, C₂–C₈ alkynyl, C₃–C₈    cycloalkyl (C₃–C₈cycloalkyl)C₁–C₃ alkyl or C₁–C₈ haloalkyl;-   R₂ is C₁–C₈ alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl, C₁–C₈ cycloalkyl or    (C₃–C₈cycloalkyl)C₁–C₃ alkyl or C₁–C₈ haloalkyl;-   R₃ is hydrogen, C₁–C₈ alkyl, C₂–C₈ alkenyl, or C₂–C₈ alkynyl;-   R₄ is C₁–C₈ alkyl, C₃–C₈ cycloalkyl, or (C₃–C₈ cycloalkyl) C₁–C₃    alkyl, each of which may be unsubstituted or substituted with one or    more substituents selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, and    mono- or di(C₁–C₆)alkylamino; or-   R₄ is phenyl, phenyl(C₁–C₄)alkyl, thienyl, pyridyl, pyrimidyl,    pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, quinazolinyl, or quinoxalinyl, each of which may be    optionally substituted or substituted with up to four groups    independently selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino; or-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,        C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino; and

-   Ar₁ and Ar₂ are independently chosen from phenyl,    phenyl(C₁–C₄)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl,    naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, and quinoxalinyl, each of which may be optionally    substituted or substituted with up to four groups independently    selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino, carboxylic acid, esters of carboxylic acids,    aminocarbonyl, mono or di(C₁–C₆)alkylaminocarbonyl,    N—(C₁–C₆)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,    and 1-piperidyl, and

-   bicyclic oxygen-containing groups of the formula:

-   -   wherein R_(B) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,        C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino.

Still additional preferred compounds of formula IX-A include thosecompounds wherein:

-   R is hydrogen, halogen, C₁–C₈ alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl,    C₁–C₈ cycloalkyl, (C₃–C₈cycloalkyl)C₁–C₃ alkyl, C₁–C₈ alkoxy, or    C₁–C₈ haloalkyl, or-   R is a phenyl which may be substituted by up to five substituents    independently chosen from C₁–C₈ alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl,    C₁–C₈ alkoxy, halogen, cyano, carboxylic acid, hydroxy, acetoxy,    nitro, amino, mono or di(C₁–C₆)alkylamino, aminocarbonyl,    sulfonamido, mono or di(C₁–C₆)alkylsulfonamido, 3,4-methylenedioxy,    3,4-(1,2-ethylene)dioxy, trifluoromethyl or trifluoromethoxy;-   R₁ is hydrogen, C₁–C₈ alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl, C₃–C₈    cycloalkyl (C₃–C₈cycloalkyl)C₁–C₃ alkyl or C₁–C₈ haloalkyl;-   R₂ is C₁–C₈ alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl, C₁–C₈ cycloalkyl or    (C₃–C₈ cycloalkyl)C₁–C₃ alkyl or C₁–C₈ haloalkyl;-   R₃ is hydrogen, C₁–C₈ alkyl, C₂–C₈ alkenyl, or C₂–C₈ alkynyl;-   R₄ is C₁–C₈ alkyl, C₃–C₈ cycloalkyl, or (C₃–C₈ cycloalkyl) C₁–C₃    alkyl, each of which may be unsubstituted or substituted with one or    more substituents selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, and    mono- or di(C₁–C₆)alkylamino; or-   R₄ is phenyl, phenyl(C₁–C₄)alkyl, thienyl, pyridyl, pyrimidyl,    pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, quinazolinyl, or quinoxalinyl, each of which may be    optionally substituted or substituted with up to four groups    independently selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino; or-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,        C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino;

-   Ar₁ is phenyl, thienyl, or pyridyl, each of which may be optionally    substituted or substituted with up to four groups independently    selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or di(C₁–C₆    alkylamino; and

-   Ar₂ is phenyl, phenyl(C₁–C₄)alkyl, thienyl, pyridyl, pyrimidyl,    pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl,    benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl,    quinolinyl, isoquinolinyl, and quinoxalinyl, each of which may be    optionally substituted or substituted with up to four groups    independently selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino, carboxylic acid, esters of carboxylic acids,    aminocarbonyl, mono or di(C₁–C₆)alkylaminocarbonyl,    N—(C₁–C₆)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,    and 1-piperidyl, or

-   Ar₂ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(B) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,        C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino.

Still further preferred compounds of formula IX above include thosewherein

-   R is hydrogen, halogen, methyl, ethyl, methoxy, ethoxy,    trifluoromethyl, or phenyl;-   R₁ is hydrogen, methyl or ethyl;-   R₂ is C₃–C₆ alkyl;-   R₃ is hydrogen, methyl or ethyl;-   R₄ is C₁–C₈ alkyl, C₃–C₈ cycloalkyl, or (C₃–C₈ cycloalkyl) C₁–C₃    alkyl, each of which may be unsubstituted or substituted with one or    more substituents selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, and    mono- or di(C₁–C₆)alkylamino; or-   R₄ is phenyl, phenyl(C₁–C₄)alkyl, thienyl, pyridyl, pyrimidyl,    pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, quinazolinyl, or quinoxalinyl, each of which may be    optionally substituted or substituted with up to four groups    independently selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino; or-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,        C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino;

-   Ar₁ is phenyl, thienyl, or pyridyl, each of which may be optionally    substituted or substituted with up to four groups independently    selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino; and

-   Ar₂ is phenyl, phenyl(C₁–C₄)alkyl, thienyl, pyridyl, pyrimidyl,    pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl,    benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl,    quinolinyl, isoquinolinyl, and quinoxalinyl, each of which may be    optionally substituted or substituted with up to four groups    independently selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino;

-   Ar₂ is a bicyclic oxygen-containing group of the formula:

wherein R_(B) represents 0 to 3 groups selected from halogen, nitro,cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,C₁–C₆ alkyl, C₂ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, and mono-or di(C₁–C₆)alkylamino.

The invention also include compounds of the following formula X:

wherein:

-   m is 0, 1, or 2;-   R is hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl,    alkoxy, mono- or dialkylamino, optionally substituted alkyl,    optionally substituted alkenyl, optionally substituted alkynyl,    optionally substituted cycloalkyl, optionally substituted    (cycloakyl)alkyl; or-   R is optionally substituted carbocyclic aryl, optionally substituted    arylalkyl, optionally substituted heteroaryl or heteroalicyclic    group having from 1 to 3 rings, 3 to 8 members in each ring and from    1 to 3 heteroatoms;-   R₁, R₂, R₃, R_(3A), R₅, and R₆ are independently selected from    hydrogen, hydrogen, halogen, amino, cyano, nitro, haloalkyl, alkoxy,    mono- or dialkylamino, optionally substituted alkyl, optionally    substituted alkenyl, optionally substituted alkynyl, optionally    substituted cycloalkyl and optionally substituted (cycloalkyl)alkyl;-   R₄ is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of    which may be optionally substituted; or-   R₄ is optionally substituted carbocyclic aryl, optionally    substituted arylalkyl, optionally substituted heteroaryl or    heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in    each ring and from 1 to 3 heteroatoms; and    Ar₁ and Ar₂ are independently optionally substituted carbocyclic    aryl, optionally substituted arylalkyl, optionally substituted    heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8    members in each ring and from 1 to 3 heteroatoms.

Preferred compounds of formula X include those of the following formulaX-A:

wherein Ar₁, R, R₁, R₂, R₃, R₄ are as defined for formula X above.

Additional preferred compounds of formula X include those wherein:

-   R₁, R₂, and R₃ are independently selected from    -   i) hydrogen, halogen, hydroxy, amino, C₁–C₆ alkoxy, mono- or        di(C₁–C₆)alkylamino, cyano, nitro, haloalkyl, and    -   ii) C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl,        and (C₃–C₈ cycloalkyl) C₁–C₃ alkyl, each of which may be        unsubstituted or substituted by one or more of halogen, nitro,        cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,        acetoxy, C₁–C₆ alkoxy, amino, mono- or di(C₁–C₆)alkylamino;-   R is selected from    -   i) hydrogen, halogen, hydroxy, amino, C₁–C₆ alkoxy, mono- or        di(C₁–C₆)alkylamino, cyano, nitro, haloalkyl, and

ii) C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl, and(C₃–C₈)cycloalkyl) C₁–C₃ alkyl, each of which may be unsubstituted orsubstituted by one or more of halogen, nitro, cyano, trifluoromethyl,trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono-or di(C₁–C₆)alkylamino; or

-   R is selected from    -   phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl,        thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,        triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of        which may be optionally substituted or substituted with up to        four groups independently selected from halogen, nitro, cyano,        trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,        C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino,        and mono- or di(C₁–C₆)alkylamino;-   R₄ is hydrogen or    -   C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈cycloalkyl, (C₃₋₈        cycloalkyl)C₁₋₄alkyl, haloalkyl, each or which may be        unsubstituted or substituted with one or more substituents        selected from halogen, nitro, cyano, trifluoromethyl,        trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino and mono- or        di(C₁–C₆)alkylamino,-   R₄ is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl,    pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,    pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,    benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono-    or di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters    of carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, —XR₅, wherein X and R_(B)    are as defined below; or-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆        alkoxy, amino, and mono- or di(C₁–C₆)alkylamino; and

-   Ar₁ and Ar₂ are independently chosen from

-   i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl,    pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,    pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,    benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono-    or di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters    of carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and —XR_(B), wherein X    and R_(B) are as defined below; and

-   ii) bicyclic oxygen-containing groups of the formula:

-   -   wherein R_(B) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆        alkoxy, amino, and mono- or di(C₁–C₆)alkylamino;

-   X is independently selected at each occurrence from the group    consisting of —CH₂—, —CHR_(C)—, —O—, —S(O)_(m)—, —NH—, —NR_(C)—,    —C(═O)NH—, —C(═O)NR_(C)—, —S(O)_(m)NH—, S(O)_(m)NR_(C)—, —NHC(═O)—,    —NR_(C)C(═O)—, —NHS(O)_(m)—, —C(═O)NHS(O)_(m)—, and —NR_(C)S(O)_(m)—    (where m is 0, 1, or 2); and

-   R_(B) and R_(C), which may be the same or different, are    independently selected at each occurrence from the group consisting    of:    -   hydrogen, straight, branched, or cyclic alkyl groups, which may        contain one or more double or triple bonds, each of which may        unsubstituted or substituted with one or more substituent(s)        selected from:        -   oxo, hydroxy, —O(C₁–C₆ alkyl), —NH(C₁–C₆ alkyl), —N(C₁–C₆            alkyl)(C₁–C₆ alkyl), —NHC(O)(C₁–C₆ alkyl), —N(C₁–C₆            alkyl)C(O)(C₁₋₆ alkyl), —NHS(O)_(x)(C₁–C₆ alkyl),            —S(O)_(x)(C₁–C₆ alkyl), —S(O)_(x)NH(C₁–C₆ alkyl),            —S(O)_(x)N(C₁–C₆ alkyl)( C₁–C₆ alkyl), (where x is 0, 1, or            2).

Additional preferred compounds of formula X above include those wherein:

-   R is hydrogen, halogen, methyl, ethyl, methoxy, ethoxy,    trifluoromethyl, or phenyl;-   R₁ is hydrogen, methyl or ethyl;-   R₂ is C₃–C₆ alkyl;-   R₃ is hydrogen, methyl or ethyl;-   R₄ is C₁–C₈ alkyl, C₃–C₈ cycloalkyl, or (C₃–C₈ cycloalkyl) C₁–C₃    alkyl, each of which may be unsubstituted or substituted with one or    more substituents selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, and    mono- or di(C₁–C₆)alkylamino; or-   R₄ is phenyl, phenyl(C₁–C₄)alkyl, thienyl, pyridyl, pyrimidyl,    pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, quinazolinyl, or quinoxalinyl, each of which may be    optionally substituted or substituted with up to four groups    independently selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino; or-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,        C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino; and

-   Ar₁ is phenyl, thienyl, or pyridyl, each of which may be optionally    substituted or substituted with up to four groups independently    selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino.

The invention also includes compounds of the following formula XI:

or pharmaceutically acceptable salt thereof, wherein:

-   n is 0, 1, or 2;-   R is chosen from hydrogen, hydroxy, halogen, amino, cyano, nitro,    haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted    alkyl, optionally substituted alkenyl, optionally substituted    alkynyl, optionally substituted cycloalkyl, optionally substituted    (cycloalkyl)alkyl,    -   optionally substituted carbocyclic aryl, optionally substituted        arylalkyl, optionally substituted heteroaryl or heteroalicyclic        group having from 1 to 3 rings, 3 to 8 members in each ring and        from 1 to 3 heteroatoms;-   R₂, R₃, R_(3A), R₅, and R₆ are independently selected from hydrogen,    hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or    dialkylamino, optionally substituted alkyl, optionally substituted    alkenyl, optionally substituted alkynyl, optionally substituted    cycloalkyl, and optionally substituted (cycloalkyl)alkyl;-   R and R₃ may be joined to form an optionally substituted saturated    carbocylic ring of from 5 to 8 members or an optionally substituted    heterocyclic ring of from 5 to 8 members;-   R₄ is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of    which may be optionally substituted; or-   R₄ is optionally substituted carbocyclic aryl, optionally    substituted arylalkyl, optionally substituted heteroaryl or    heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in    each ring and from 1 to 3 heteroatoms; and-   Ar₁ and Ar₂ are independently optionally substituted carbocyclic    aryl, optionally substituted arylalkyl, optionally substituted    heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8    members in each ring and from 1 to 3 heteroatoms.

The invention further includes compounds of the following formula XII:

or a pharmaceutically acceptable salt thereof, wherein:

-   R is chosen from hydrogen, hydroxy, halogen, amino, cyano, nitro,    haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted    alkyl, optionally substituted alkenyl, optionally substituted    alkynyl, optionally substituted cycloalkyl, optionally substituted    (cycloalkyl)alkyl,    -   optionally substituted carbocyclic aryl, optionally substituted        arylalkyl, optionally substituted heteroaryl or heteroalicyclic        group having from 1 to 3 rings, 3 to 8 members in each ring and        from 1 to 3 heteroatoms;-   R₂ and R₃ are independently selected from hydrogen, hydroxy,    halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or    dialkylamino, optionally substituted alkyl, optionally substituted    alkenyl, optionally substituted alkynyl, optionally substituted    cycloalkyl, and optionally substituted (cycloalkyl)alkyl;-   R and R₃ may be joined to form an optionally substituted carbocylic    ring of from 5 to 8 members or an optionally substituted    heterocyclic ring of from 5 to 8 members;-   R₄ is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of    which may be optionally substituted; or-   R₄ is optionally substituted carbocyclic aryl, optionally    substituted arylalkyl, optionally substituted heteroaryl or    heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in    each ring and from 1 to 3 heteroatoms; and-   Ar₁ and Ar₂ are independently optionally substituted carbocyclic    aryl, optionally substituted arylalkyl, optionally substituted    heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8    members in each ring and from 1 to 3 heteroatoms.

Preferred compounds of formula XII above include wherein R and R₃ arenot joined.

Also preferred are compounds of formula XII wherein:

-   R is selected from    -   i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or        dialkylamino, cyano, nitro, haloalkyl, and    -   ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl,        each of which may be unsubstituted or substituted by one or more        of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,        haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or        dialkylamino,    -   iii) phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl,        thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,        triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of        which may be substituted with up to four groups independently        selected from halogen, nitro, cyano, trifluoromethyl,        trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl,        alkynyl, alkoxy, amino, and mono- or dialkylamino;-   R₂ and R₃ are independently selected from    -   i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or        dialkylamino, cyano, nitro, haloalkyl, and    -   ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl,        each of which may be unsubstituted or substituted by one or more        of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,        haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or        dialkylamino;-   R₄ is hydrogen or    -   alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,        haloalkyl, each or which may be unsubstituted or substituted        with one or more substituents selected from halogen, nitro,        cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,        acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino and mono- or        dialkylamino,-   R₄ is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl,    pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,    pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,    benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino,    aminoalkoxy, carboxylic acid, esters of carboxylic acids,    aminocarbonyl, mono or dialkylaminocarbonyl,    N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,    1-piperidyl and —XR_(B), wherein X and R_(B) are as defined below;    or-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and        mono- or dialkylamino;

-   Ar₁ and Ar₂ are independently chosen from

-   i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl,    pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,    pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,    benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino,    aminoalkoxy, carboxylic acid, esters of carboxylic acids,    aminocarbonyl, mono or dialkylaminocarbonyl,    N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,    1-piperidyl and —XR_(B), wherein X and R_(B) are as defined below;    and

-   ii) bicyclic oxygen-containing groups of the formula:

-   -   wherein R_(B) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and        mono- or dialkylamino;

-   X is independently selected at each occurrence from the group    consisting of —CH₂—, —CHR_(C)—, —O—, —S(O)_(m)—, —NH—, —NR_(C)—,    —C(═O)NH—, —C(═O)NR_(C)—, S(O)_(m)NH—, S(O)_(m)NR_(C)—, —NHC(═O)—,    —NR_(C)C(═O)—, —NHS(O)_(m)—, C(═O)NHS(O)_(m)—, and —NR_(C)S(O)_(m)—    (where m is 0, 1, or 2); and

-   R_(B) and R_(C), which may be the same or different, are    independently selected at each occurrence from the group consisting    of:    -   hydrogen, straight, branched, or cyclic alkyl groups, which may        contain one or more double or triple bonds, each of which may        unsubstituted or substituted with one or more substituent(s)        selected from:        -   oxo, hydroxy, —O(alkyl), —NH(alkyl), —N(alkyl)(alkyl),            —NHC(O)(alkyl), —N(alkyl)C(O)(alkyl), —NHS(O)_(x)(alkyl),            —S(O)_(x)(alkyl), —S(O)_(x)NH(alkyl),            —S(O)_(x)N(alkyl)(alkyl), (where x is 0, 1, or 2).

Additional preferred compounds of formula XII include those wherein:

-   R is selected from    -   i) hydrogen, halogen, hydroxy, amino, C₁–C₆ alkoxy, mono- or        di(C₁–C₆)alkylamino, cyano, nitro, haloalkyl, and    -   ii) C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl,        and (C₃–C₈)cycloalkyl) C₁–C₃ alkyl, each of which may be        unsubstituted or substituted by one or more of halogen, nitro,        cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,        acetoxy, alkoxy, amino, and mono- or di(C₁–C₆)alkylamino,    -   iii) phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl,        thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,        triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of        which may be optionally substituted or substituted with up to        four groups independently selected from halogen, nitro, cyano,        trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,        C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino,        and mono- or di(C₁–C₆)alkylamino;-   R₂ and R₃ are independently selected from    -   i) hydrogen, halogen, hydroxy, amino, C₁–C₆ alkoxy, mono- or        di(C₁–C₆)alkylamino, cyano, nitro, haloalkyl, and    -   ii) C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl,        and (C₃–C₈ cycloalkyl) C₁–C₃ alkyl, each of which may be        unsubstituted or substituted by one or more of halogen, nitro,        cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,        acetoxy, C₁–C₆ alkoxy, amino, mono- or di(C₁–C₆)alkylamino;-   R₄ is hydrogen or    -   C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈cycloalkyl, (C₃₋₈        cycloalkyl)C₁₋₄alkyl, haloalkyl, each or which may be        unsubstituted or substituted with one or more substituents        selected from halogen, nitro, cyano, trifluoromethyl,        trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino and mono- or        di(C₁–C₆)alkylamino,-   R₄ is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl,    pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,    pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,    benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono-    or di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters    of carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, —XR_(B), wherein X and    R_(B) are as defined below; or-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆        alkoxy, amino, and mono- or di(C₁–C₆)alkylamino;

-   Ar₁ and Ar₂ are independently chosen from

-   i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl,    pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,    pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,    benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,    benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,    isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of    which may be optionally substituted or substituted with up to four    groups independently selected from halogen, nitro, cyano,    trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,    C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono-    or di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters    of carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and —XR_(B), wherein X    and R_(B) are as defined below; and

-   ii) bicyclic oxygen-containing groups of the formula:

-   -   wherein R_(B) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆        alkoxy, amino, and mono- or di(C₁–C₆)alkylamino;

-   X is independently selected at each occurrence from the group    consisting of —CH₂—, —CHR_(C)—, —O—, —S(O)_(m)—, —NH—, —NR_(C)—,    —C(═O)NH—, —C(═O)NR_(C)—, —S(O)_(m)NH—, —S(O)_(m)NR_(C)—, —NHC(═O)—,    —NR_(C)C(═O)—, —NHS(O)_(m)—, —C(═O)NHS(O)_(m)—, and —NR_(C)S(O)_(m)—    (where m is 0, 1, or 2); and

-   R_(B) and R_(C), which may be the same or different, are    independently selected at each occurrence from the group consisting    of:    -   hydrogen, straight, branched, or cyclic alkyl groups, which may        contain one or more double or triple bonds, each of which may        unsubstituted or substituted with one or more substituent(s)        selected from:        -   oxo, hydroxy, —O(C₁–C₆ alkyl), —NH(C₁–C₆ alkyl), —N(C₁–C₆            alkyl)(C₁–C₆ alkyl), —NHC(O)(C₁–C₆ alkyl), —N(C₁–C₆            alkyl)C(O)(C₁₋₆ alkyl), —NHS(O)_(x)(C₁–C₆ alkyl),            —S(O)_(x)(C₁–C₆ alkyl), —S(O)_(x)NH(C₁–C₆ alkyl),            —S(O)_(x)N(C₁–C₆ alkyl)(C₁–C₆ alkyl), (where x is 0, 1, or            2).

Also preferred are compounds of formula XII wherein:

-   R is hydrogen, halogen, hydroxy, C₁–C₆ alkoxy, haloalkyl, C₁–C₈    alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl, and    (C₃–C₈)cycloalkyl) C₁–C₃ alkyl, or-   R is phenyl substituted with up to five groups independently    selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₈ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, and mono- or    di(C₁–C₆)alkylamino, aminocarbonyl, sufonamido, mono or    di(C₁–C₆)alkylsulfonamido, 3,4-methylenedioxy, and    3,4-(1,2-ethylene)dioxy;-   R₂ is selected from C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈    cycloalkyl, (C₃–C₈ cycloalkyl) C₁–C₃ alkyl and haloalkyl;-   R₃ is hydrogen C₁–C₈ alkyl, C₂–C₄ alkenyl, C₂–C₆ alkynyl;-   R₄ is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈cycloalkyl, (C₃₋₈    cycloalkyl)C₁₋₄alkyl, haloalkyl, each or which may be unsubstituted    or substituted with one or more substituents selected from halogen,    nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,    acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy,    amino and mono- or di(C₁–C₆)alkylamino,-   R₄ is phenyl, phenyl(C₁–C₄)alkyl, thienyl, pyridyl, pyrimidyl,    pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl,    indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl,    benzodioxolyl, benz[d]isoxazolyl, each of which may be substituted    with up to five groups independently selected from halogen, nitro,    cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,    acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy,    amino, mono- or di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic    acid, esters of carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl,-   R₄ is a bicyclic oxygen-containing group of the formula:

-   -   wherein R_(A) represents 0 to 3 groups selected from halogen,        nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,        hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆        alkoxy, amino, and mono- or di(C₁–C₆)alkylamino;

-   Ar₁ and Ar₂ are independently chosen from

-   i) phenyl, phenyl(C₁–C₄)alkyl, thienyl, pyridyl, pyrimidyl,    pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl,    indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl,    benzodioxolyl, and benz[d]isoxazolyl, each of which may be    optionally substituted or substituted with up to four groups    independently selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters of    carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or

-   ii) bicyclic oxygen-containing groups of the formula:

wherein R_(B) represents 0 to 3 groups selected from halogen, nitro,cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, and mono-or di(C₁–C₆)alkylamino.

Also preferred are compounds of formula XII wherein:

-   R, R₂, R₃, R₄, and Ar₂ are as defined in formula XII;-   Ar₁ is phenyl with up to four groups independently selected from    halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,    hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆    alkoxy, amino, mono- or di(C₁–C₆)alkylamino, and amino(C₁–C₆)alkoxy.

Also preferred are compounds of formula XII wherein:

-   R, R₂, and R₃ are as defined in formula XII;-   Ar₁ is phenyl with up to four groups independently selected from    halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,    hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆    alkoxy, amino, mono- or di(C₁–C₆)alkylamino, and amino(C₁–C₆)alkoxy;-   R₄ is C₃–C₈ alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl, C₃–C₈cycloalkyl,    (C₃₋₈ cycloalkyl)C₁–C₄alkyl, C₁–C₈ haloalkyl, each or which may be    unsubstituted or substituted with one or more substituents selected    from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,    haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁–C₆ alkoxy, amino and mono- or di(C₁–C₆)alkylamino,-   R₄ is phenyl, phenyl(C₁–C₄)alkyl, thienyl, pyridyl, pyrimidyl,    pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl,    indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl,    benzodioxolyl, benz[d]isoxazolyl, each of which may be optionally    substituted or substituted with up to four groups independently    selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters of    carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl;-   Ar₂ is phenyl, phenyl(C₁–C₄)alkyl, thienyl, pyridyl, pyrimidyl,    pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl,    indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl,    benzodioxolyl, or benz[d]isoxazolyl, each of which may be optionally    substituted or substituted with up to four groups independently    selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters of    carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or-   Ar₂ is bicyclic oxygen-containing groups of the formula:

wherein R_(B) represents 0 to 3 groups selected from halogen, nitro,cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, and mono-or di(C₁–C₆)alkylamino.

Also preferred are compounds of formula XII wherein:

-   R is hydrogen, C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈    cycloalkyl, or (C₃–C₈)cycloalkyl) C₁–C₃ alkyl, or-   R is phenyl substituted with up to five groups independently    selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₈ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, and mono- or    di(C₁–C₆)alkylamino, aminocarbonyl, sufonamido, mono or    di(C₁–C₆)alkylsulfonamido, 3,4-methylenedioxy, and    3,4-(1,2-ethylene)dioxy;-   R₂ is C₃–C₆ alkyl;-   R₃ is hydrogen, methyl, or ethyl;-   R₄ is C₃–C₈ alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl, C₃–C₈cycloalkyl,    (C₃₋₈ cycloalkyl)C₁–C₄alkyl, C₁–C₈ haloalkyl, each or which may be    unsubstituted or substituted with one or more substituents selected    from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,    haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁–C₆ alkoxy, amino and mono- or di(C₁–C₆)alkylamino,-   R₄ is phenyl, phenyl(C₁–C₄)alkyl, thienyl, pyridyl, pyrimidyl,    pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl,    indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl,    benzodioxolyl, benz[d]isoxazolyl, each of which may be optionally    substituted or substituted with up to four groups independently    selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters of    carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl;-   Ar₁ is phenyl with up to four groups independently selected from    halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,    hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆    alkoxy, amino, mono- or di(C₁–C₆)alkylamino, and amino(C₁–C₆)alkoxy;-   Ar₂ is phenyl, phenyl(C₁–C₄)alkyl, thienyl, pyridyl, pyrimidyl,    pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl,    indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl,    benzodioxolyl, or benz[d]isoxazolyl, each of which may be optionally    substituted or substituted with up to four groups independently    selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters of    carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or-   Ar₂ is bicyclic oxygen-containing groups of the formula:

wherein R_(B) represents 0 to 3 groups selected from halogen, nitro,cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, and mono-or di(C₁–C₆)alkylamino.

Also preferred are compounds of formula XII wherein:

-   R is hydrogen, C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈    cycloalkyl, or (C₃–C₈)cycloalkyl) C₁–C₃ alkyl, or phenyl;-   R₂ is C₃–C₆ alkyl;-   R₃ is hydrogen, methyl, or ethyl;-   R₄ is C₃–C₈ alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl, C₃–C₈cycloalkyl,    (C₃₋₈ cycloalkyl)C₁–C₄alkyl, C₁–C₈ haloalkyl, each or which may be    unsubstituted or substituted with one or more substituents selected    from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,    haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁–C₆ alkoxy, amino and mono- or di(C₁–C₆)alkylamino;-   Ar₁ is phenyl with up to four groups independently selected from    halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,    hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆    alkoxy, amino, mono- or di(C₁–C₆)alkylamino, and amino(C₁–C₆)alkoxy;    and-   Ar₂ is phenyl, phenyl(C₁–C₄)alkyl, thienyl, pyridyl, pyrimidyl,    pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl,    indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl,    benzodioxolyl, or benz[d]isoxazolyl, each of which may be optionally    substituted or substituted with up to four groups independently    selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆    alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters of    carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or-   Ar₂ is bicyclic oxygen-containing groups of the formula:

wherein R_(B) represents 0 to 3 groups selected from halogen, nitro,cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, and mono-or di(C₁–C₆)alkylamino.

Also preferred are compounds of formula XII wherein:

-   R is hydrogen, C₁–C₈ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈    cycloalkyl, or (C₃–C₈)cycloalkyl) C₁–C₃ alkyl, or phenyl;-   R₂ is C₃–C₆ alkyl;-   R₃ is hydrogen, methyl, or ethyl;-   R₄ is phenyl, phenyl(C₁–C₄)alkyl, thienyl, pyridyl, pyrimidyl,    pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl,    indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl,    benzodioxolyl, benz[d]isoxazolyl, each of which may be optionally    substituted or substituted with up to four groups independently    selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters of    carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl;-   Ar₁ is phenyl with up to four groups independently selected from    halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,    hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆    alkoxy, amino, mono- or di(C₁–C₆)alkylamino, and amino(C₁–C₆)alkoxy;-   Ar₂ is phenyl, phenyl(C₁–C₄)alkyl, thienyl, pyridyl, pyrimidyl,    pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl,    indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl,    benzodioxolyl, or benz[d]isoxazolyl, each of which may be optionally    substituted or substituted with up to four groups independently    selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters of    carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or-   Ar₂ is bicyclic oxygen-containing groups of the formula:

wherein R_(B) represents 0 to 3 groups selected from halogen, nitro,cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, and mono-or di(C₁–C₆)alkylamino.

The invention also includes compounds of the following formula XIII:

or a pharmaceutically acceptable salt thereof, wherein:

-   n is 1, 2, or 3

-    represents a carbon chain that may be substituted with hydrogen,    halogen, cyano, nitro amino, mono or dialkyl amino, alkenyl,    alkynyl, alkoxy, trifluoromethyl, trifluoromethoxy, straight or    branched chain alkyl, or cycloalkyl, and n is 1, 2, or 3;-   Ar₁, Ar₂, and Ar₃ are independently optionally substituted    carbocyclic aryl, optionally substituted arylalkyl, optionally    substituted heteroaryl or heteroalicyclic group having from 1 to 3    rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and-   R₁ represents up to 4 groups independently chosen from hydrogen,    halogen, hydroxy, amino, alkoxy, acetoxy, mono- or dialkylamino,    cyano, nitro, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl,    (cycloalkyl)alkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH₂),    mono or dialkylaminocarbonyl, sulfonamido, and mono or    dialkylsulfonamido.

Also preferred are compounds of formula XIII wherein

n, m, and R₁ are defined as for formula XIII above;

-   Ar₁ and Ar₃ are independently chosen from phenyl, pyridyl, and    pyrimidinyl each of which is optionally substituted or substituted    with up to 4 groups independently chosen from hydrogen, halogen,    hydroxy, amino, C₁–C₆ alkoxy, acetoxy, mono- or di(C₁–C₆)alkylamino,    cyano, nitro, C₁–C₆ haloalkyl, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆    alkynyl, C₃–C₈ cycloalkyl, (C₃–C₈cycloalkyl) C₁–C₃ alkyl, hydroxy    carbonyl (COOH), aminocarbonyl (CONH₂), mono or    di(C₁–C₆)alkylaminocarbonyl, sulfonamido, 3,4-methylenedioxy,    ethylenedioxy, and mono or di(C₁–C₆)alkylsulfonamido; and-   Ar₂ represents suberanyl, indanyl, tetrhydronaphtyl, or indolyl,    each of which is optionally substituted or substituted with up to 4    groups independently chosen from hydrogen, halogen, hydroxy, amino,    C₁–C₆ alkoxy, acetoxy, mono- or di(C₁–C₆alkylamino, cyano, nitro,    C₁–C₆ haloalkyl, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈    cycloalkyl, (C₃–C₈cycloalkyl) C₁–C₃ alkyl, hydroxy carbonyl (COOH),    aminocarbonyl (CONH₂), mono or di(C₁–C₆)alkylaminocarbonyl,    sulfonamido, 3,4-methylenedioxy, ethylenedioxy, and mono or    di(C₁–C₆)alkylsulfonamido.

Also preferred are compounds of formula XIII above wherein:

R₁, R₃, and R₅ each represent up to 4 groups independently chosen fromhydrogen, halogen, hydroxy, amino, C₁–C₆ alkoxy, acetoxy, mono- ordi(C₁–C₆)alkylamino, cyano, nitro, C₁–C₆ haloalkyl, C₁–C₆ alkyl, C₂–C₆alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl, (C₃–C₈cycloalkyl) C₁–C₃ alkyl,hydroxy carbonyl (COOH), aminocarbonyl (CONH₂), mono ordi(C₁–C₆)alkylaminocarbonyl, sulfonamido, and mono ordi(C₁–C₆)alkylsulfonamido; and represents suberanyl, indanyl,tetrhydronaphtyl, or indolyl, each of which is optionally optionallysubstituted or substituted with up to 4 groups independently chosen fromhydrogen, halogen, hydroxy, amino, C₁–C₆ alkoxy, acetoxy, mono- ordi(C₁–C₆)alkylamino, cyano, nitro, C₁–C₆ haloalkyl, C₁–C₆ alkyl, C₂–C₆alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl, (C₃–C₈ cycloalkyl) C₁–C₃alkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH₂), mono ordi(C₁–C₆)alkylaminocarbonyl, sulfonamido, 3,4-methylenedioxy,ethylenedioxy, and mono or di(C₁–C₆)alkylsulfonamido.

The invention also includes compounds of the following formula XIV:

or a pharmaceutically acceptable salt, thereof, wherein:

-   R represents up to 4 groups independently chosen from hydrogen,    halogen, hydroxy, amino, alkoxy, acetoxy, mono- or dialkylamino,    cyano, nitro, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl,    (cycloalkyl)alkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH₂),    mono or di(C₁–C₆)alkylaminocarbonyl, sulfonamido,    3,4-methylenedioxy, ethylenedioxy, and mono or dialkylsulfonamido;-   R₁ is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of    which may be optionally substituted; or-   R₁ is optionally substituted carbocyclic aryl, optionally    substituted arylalkyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted heteroarylalkyl,    or an optionally substituted heteroalicyclic or heteroalicyclicalkyl    group having from 1 to 3 rings, 3 to 8 members in each ring and from    1 to 3 heteroatoms; and-   Ar₁ and Ar₂ are independently optionally substituted carbocyclic    aryl, optionally substituted arylalkyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, or an optionally    substituted heteroalicyclic or heteroalicyclicalkyl group having    from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3    heteroatoms.

Preferred compounds of formula XIV include those (referred to herein ascompounds of formula XIV-A) wherein

-   R represents up to 4 groups independently chosen from hydrogen,    halogen, hydroxy, amino, C₁–C₆ alkoxy, acetoxy, mono- or    di(C₁–C₆)alkylamino, cyano, nitro, C₁–C₆ haloalkyl, C₁–C₆ alkyl,    C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl, (C₃–C₈ cycloalkyl)    C₁–C₃ alkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH₂), mono or    di(C₁–C₆)alkylaminocarbonyl, sulfonamido, 3,4-methylenedioxy,    ethylenedioxy, and mono or di(C₁–C₆)alkylsulfonamido;-   R₁ is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈cycloalkyl, (C₃₋₈    cycloalkyl)C₁₋₄alkyl, each or which may be unsubstituted or    substituted with one or more substituents selected from halogen,    nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,    acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy,    amino and mono- or di(C₁–C₆)alkylamino, or-   R₁ is phenyl, phenylalkyl, chromanyl, chromanylalkyl, imidazolyl,    imidazolylalkyl, pyridyl, pyridylalkyl, pyrimidyl, pyrimdylalkyl,    pyrazinyl, pyrazinylalkyl, indolyl, indolylalkyl, indanyl,    indanylalkyl, benzodioxolylalkyl, or benzodioxolyl, each of which    may be optionally substituted or substituted with up to four groups    independently selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters of    carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,    1-azetidinyl, 1-pyrrolidinyl, and 1-piperidyl;-   Ar₁ is chosen from phenyl, pyrrolyl, imidazolyl, pyrazolyl,    triazolyl, thiophenyl, and pyridyl, each of which may be optionally    substituted or substituted with up to four groups independently    selected from halogen, nitro, cyano, trifluoromethyl,    trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono- or    di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters of    carboxylic acids, aminocarbonyl, mono or    di(C₁–C₆)alkylaminocarbonyl, and    N—(C₁–C₆)alkylsulfonylaminocarbonyl; and-   Ar₂ is chosen from phenyl, phenylalkyl, chromanyl, chromanylalkyl,    pyrrolyl, pyrrolylalkyl, furanyl, furanylalkyl, thienyl,    thienylalkyl, pyridyl, pyridylalkyl, pyrimidyl, pyrimidylalkyl,    pyrazinyl, pyrazinylalkyl, benzimidazolyl, benzimidazolylalkyl,    imidazopyrdinyl, imidazopyrdinylalkyl, naphthyl, napthylalkyl,    indolyl, indolylalkyl, indanyl, indanylalkyl, benzofuranyl,    benzofuranylalkyl, benzodioxinyl, benzodioxinylalkyl, benzodioxolyl,    benzodioxolylalkyl, quinolinyl, quinolinylalkyl, isoquinolinyl,    isoquinolinylalkyl, each of which may be optionally substituted or    substituted with up to four groups independently selected from:    -   halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,        haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₁–C₆ alkoxy, amino, mono- or di(C₁–C₆)alkylamino,        mono- or di(C₁–C₆)alkylamino(C₁–C₆)alkyl, amino(C₁–C₆)alkoxy,        C₁–C₆ alkoxyC₁–C₆ alkyl, C₁–C₆ alkoxyC₁–C₆ alkoxy, carboxylic        acid, esters of carboxylic acids, aminocarbonyl, mono or        di(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)        alkylsulfonylaminocarbonyl,    -   benzyl (which may be unsubstituted or substituted with one or        more substituents independently chosen from halogen, C₁–C₆alkyl,        and C₁–C₆alkoxy),    -   —C₁–C₆ alkyl NR₂R₃ or —C₁–C₆alkoxy NR₂R₃ wherein the point of        attachment to Ar₂ is at the C₁–C₆ alkyl or C₁–C₆ alkoxy, and R₂        and R₃ are hydrogen, or straight or branched chain alkyl and are        optionally substituted with halogen, hydroxy, or C₁–C₆ alkoxy        and R₂ and R₃ may be taken together with the nitrogen to which        they are attached to form a heterocycloalkyl group.

Preferred compounds of formula XIV-A include those wherein:

wherein:

-   Ar₂ is as defined in Claim in formula XIV-A;-   R_(X) represents up to 4 groups independently chosen from hydrogen,    halogen, hydroxy, amino, C₁–C₆ alkoxy, acetoxy, mono- or    di(C₁–C₆)alkylamino, cyano, nitro, C₁–C₆ haloalkyl, C₁–C₆ alkyl,    C₂–C₆ alkenyl, and C₂–C₆ alkynyl; and-   R₁ is C₁–C₆alkyl, C₃–C₈cycloalkyl, (C₃–C₈ cycloalkyl)C₁–C₄alkyl,    phenyl, phenyl, C₁–C₆alkyl, chromanyl, chromanylC₁–C₆alkyl,    imidazolyl, imidazolylC₁–C₆alkyl, pyridyl, pyridylC₁–C₆alkyl,    pyrimidyl, pyrimidylC₁–C₆alkyl,pyrazinyl, pyrazinylC₁–C₆alkyl,    indolyl, indolylC₁–C₆alkyl, indanyl, indanylC₁–C₆alkyl,    benzodioxolyl, or benzodioxolylC₁–C₆alkyl each or which may be    unsubstituted or substituted with up to 4 substituents selected from    halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,    hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆    alkoxy, amino and mono- or di(C₁–C₆)alkylamino.

Additional preferred compounds of formula XIV-A includes those of thefollowing formula:

wherein:

-   R_(X) represents up to 4 groups independently chosen from hydrogen,    halogen, hydroxy, amino, C₁–C₆ alkoxy substituted with 0–2 R₂,    acetoxy, mono- or di(C₁–C₆)alkylamino, cyano, nitro, C₁–C₆    haloalkyl, C₁–C₆ alkyl, C₂–C₆ alkenyl, and C₂–C₆ alkynyl;-   R₁ is phenyl, phenylC₁–C₆ alkyl, C₃–C₈ cycloalkyl, C₃–C₈    cycloalky(C₁–C₄ alkyl), naphthyl, napthylC₁–C₆alkyl, indanyl,    indanylC₁–C₆ alkyl, benzodioxolanyl, or benzodioxolanylC₁–C₆ alkyl,    each of which may be substituted by up to 4 groups chosen from    halogen, hydroxy, amino, C₁–C₆ alkoxy, acetoxy, mono- or    di(C₁–C₆)alkylamino, cyano, nitro, C₁–C₆ haloalkyl, C₁–C₆ alkyl; and

Ar₂ represents phenyl, benzyl, indanyl, indanyl-CH₂—, benzodioxolanyl,or benzodioxolanyl-CH₂—; each of which is substituted by up to 4 groupsindependently chosen from hydrogen, halogen, hydroxy, amino, C₁–C₆alkoxy, acetoxy, mono- or di(C₁–C₆)alkylamino, cyano, nitro, C₁–C₆haloalkyl, C₁–C₆ alkyl, C₂–C₆ alkenyl, and C₂–C₆ alkynyl.

Additional preferred compounds of formula XIV includes those wherein:

-   Ar₂ is as defined for formula XIV;-   R represents up to 4 groups independently chosen from hydrogen,    halogen, amino, C₁–C₆ alkoxy, C₁–C₆ alkyl, trifluoromethyl, and    trifluoromethoxy;-   R₁ is phenyl, benzyl, C₃–C₈ cycloalkyl, C₃–C₈ cycloalkyl(C₁–C₄    alkyl), naphthyl, naphthyl-CH₂—, indanyl, indandyl-CH₂—,    benzodioxolanyl-CH₂—, or benzodioxolanyl, each of which may be    substituted by up to 4 groups chosen from halogen, hydroxy, amino,    C₁–C₆ alkoxy, acetoxy, mono- or di(C₁–C₆)alkylamino, cyano, nitro,    C₁–C₆ haloalkyl, C₁–C₆ alkyl; and-   Ar₁ is chosen from pyrrolyl, imidazolyl, pyrazolyl, triazolyl,    thiophenyl, each of which may be optionally substituted or    substituted with up to four groups independently selected from    halogen, trifluoromethyl, trifluoromethoxy, C₁–C₆ alkoxy, C₁–C₆    alkyl, and amino.

Also preferred are compounds of the formula XIV above wherein:

-   R represents up to 4 groups independently chosen from hydrogen,    halogen, amino, C₁–C₆ alkoxy, C₁–C₆ alkyl, trifluoromethyl, and    trifluoromethoxy;-   R₁ is benzyl which is unsubstituted or substituted by up to 4 groups    chosen from halogen, hydroxy, amino, C₁–C₆ alkoxy, acetoxy, mono- or    di(C₁–C₆)alkylamino, cyano, nitro, C₁–C₆ haloalkyl, C₁–C₆ alkyl;-   Ar₁ is chosen from pyrrolyl, imidazolyl, pyrazolyl, triazolyl,    thiophenyl, each of which may be optionally substituted or    substituted with up to four groups independently selected from    halogen, trifluoromethyl, trifluoromethoxy, C₁–C₆ alkoxy, C₁–C₆    alkyl, and amino; and-   Ar₂ is chosen from phenyl, benzyl, indolyl, indolyl-CH₂—, indanyl,    indanyl-CH₂—, chromanyl, chromanyl-CH₂—, benzofuranyl,    benzofuranyl-CH₂—, benzodioxinyl, benzodioxinyl-CH₂—,    benzodioxolyl-CH₂—, and benzodioxolyl, each of which may be    optionally substituted or substituted with up to four groups    independently selected from:    -   halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,        haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino.

Preferred compounds of formula XIV also include those of the followingformula IV-B:

wherein:

-   m is 0, 1, 2, or 3, and

-    represents a carbon chain which is optionally substituted with    methyl, ethyl, methoxy, ethoxy, hydoxy, halogen, or amino;-   R represents up to 4 groups independently chosen from hydrogen,    halogen, hydroxy, amino, C₁–C₆alkyl, C₂–C₆ alkenyl, C₁–C₆ alkynyl,    C₁–C₆ alkoxy, acetoxy, mono- or di(C₁–C₆)alkylamino;-   R_(X) and R_(Y) each represent up to 4 groups independently chosen    from hydrogen, halogen, hydroxy, amino, C₁–C₆ alkoxy, acetoxy, mono-    or di(C₁–C₆)alkylamino, cyano, nitro, C₁–C₆ haloalkyl, C₁–C₆ alkyl,    C₂–C₆ alkenyl, and C₂–C₆ alkynyl; and-   R₁ and R₄ are independently selected from C₁–C₆alkyl,    C₃–C₈cycloalkyl, (C₃–C₈ cycloalkyl)C₁–C₄alkyl, phenyl,    phenylC₁–C₆alkyl, pyridyl, and pyridylC₁–C₆alkyl, each or which may    be unsubstituted or substituted with up to 4 substituents selected    from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,    haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁–C₆ alkoxy, amino and mono- or di(C₁–C₆)alkylamino.

The invention also provides compounds of the following formula XV:

or a pharmaceutically acceptable salt thereof, wherein;

-   m is 0, 1, 2, or 3, and

-    represents a carbon chain which is optionally substituted with    methyl, ethyl, methoxy, ethoxy, hydoxy, halogen, or amino;-   n is 0, 1, 2, or 3, and

-    represents a carbon chain which is optionally substituted with    methyl, ethyl, methoxy, ethoxy, hydoxy, halogen, or amino;-   R represents up to 4 groups independently chosen from hydrogen,    halogen, hydroxy, amino, alkoxy, acetoxy, mono- or dialkylamino,    cyano, nitro, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, and    (cycloalkyl)alkyl;-   R₂ is    -   i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or        dialkylamino, cyano, nitro, haloalkyl, and    -   ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl) alkyl,        each of which may be unsubstituted or substituted by one or more        of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,        haloalkyl, hydroxy, acetoxy, alkoxy, amino, mono- or        dialkylamino; and-   Ar₁ and Ar₂ are independently optionally substituted carbocyclic    aryl, optionally substituted arylalkyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkyl, or an optionally substituted    heteroalicyclic or heteroalicyclicalkyl group having from 1 to 3    rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.

Preferred compounds of formula XV include those of the followingformula:

-   m is 1 and

-    represents a carbon chain which is unsubstituted;-   n is 1 and

-    represents a carbon chain which is unsubstituted;-   R represents up to 4 groups independently chosen from hydrogen,    halogen, hydroxy, amino, C₁–C₆ alkoxy, acetoxy, mono- or    di(C₁–C₆)alkylamino, cyano, nitro, C₁–C₆ haloalkyl, C₁–C₆ alkyl,    C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₂–C₆ cycloalkyl, and (C₃–C₈    cycloalkyl) C₁–C₄ alkyl;-   R₂ is C₃–C₈ alkyl or C₃–C₈ cycloalkyl;-   Ar₁ and Ar₂ are independently chosen from phenyl,    phenyl(C₁–C₄)alkyl, pyrrolyl, furanyl, thienyl, pyrazolyl,    imidazolyl, thiazolyl, pyridyl, pyrimidyl, and pyrazinyl, each of    which may be unsubstituted or optionally substituted or substituted    with up to four groups independently selected from halogen, nitro,    cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,    acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy,    amino, mono- or di(C₁–C₆)alkylamino.

Compounds of the invention may have one or more asymmetric centers orplanes. Compounds of the present invention containing an asymmetricallysubstituted atom may be isolated in optically active or racemic forms.It is well known in the art how to prepare optically active forms, suchas by resolution of racemic forms (racemates), by asymmetric synthesis,or by synthesis from optically active starting materials. Resolution ofthe racemates can be accomplished, for example, by conventional methodssuch as crystallization in the presence of a resolving agent, orchromatography, using, for example a chiral HPLC column. Many geometricisomers of olefins, C═N double bonds, and the like can also be presentin the compounds described herein, and all such stable isomers arecontemplated in the present invention. Cis and trans geometric isomersof the compounds of the present invention are described and may beisolated as a mixture of isomers or as separated isomeric forms. Allchiral (enantiomeric and diastereomeric), and racemic forms, as well asall geometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

Some compounds of the invention may exist as tautomers. Unless otherwisespecified any description or claim of one tautomeric form is intended toencompass the other tautomer.

Specifically preferred compounds include those shown in the FIGS. 1through 6. In those figures, the substituent X depicts the moietylinkage to the base compound whose structure is shown at the top of eachFigure.

Additional preferred compounds of the invention include the following(compounds structures are shown directly above the compound chemicalname in many instances):

-   1-(1-butyl)-2-phenyl-5-(N,N-di[3,4-methylenedioxyphenyl    methyl])aminomethylimidazole;-   1-(1-butyl)-2-phenyl-5-(1-[N-{3,4-methylenedioxyphenylmethyl}-N-phenylmethyl]amino)ethylimidazole;-   1-Butyl-2-phenyl-4-bromo-5-(N-phenylmethyl-N-[1-butyl])aminomethylimidazole;-   1-(1-Butyl)-2-phenyl-4-methyl-5-(N-[3,4-methylenedioxyphenyl-methyl]-N-phenylmethyl)aminomethylimidazole;-   1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[1,4-benzodioxan-6-yl]methyl-N-phenylmethyl)    aminomethylimidazole;-   1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)    aminomethylimidazole;-   1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[1,4-benzodioxan-6-yl]methyl-N-phenylmethyl)    aminomethylimidazole;

-   1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)    aminomethylimidazole;

-   1-(1-Butyl)-2-(2-fluorophenyl)-5-(N-[1,4-benzodioxan-6-ylmethyl]-N-phenylmethyl)amino-methylimidazole;

-   1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N-[naphtha-2-ylmethyl]-N-phenylmethyl)amino-methylimidazole;

-   1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)    aminomethylimidazole;

-   1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])    aminomethylimidazole;

-   1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N-[4-dimethylaminophenylmethyl]-N-phenylmethyl)    aminomethylimidazole;

-   1-(1-Butyl)-2-(2-methylphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)    aminomethylimidazole;

-   1-(1-Butyl)-2-(4-fluorophenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])amino-methylimidazole;

-   1-(1-Butyl)-2-(2-methylphenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])amino-methylimidazole;

-   1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-[naphth-2-ylmethyl]-N-phenylmethyl)amino    methylimidazole;

-   1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)    aminomethylimidazole;

-   1-(1-Butyl)-2-(3-fluorophenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])amino-methylimidazole;

-   1-(1-Butyl)-2-(3-methoxyphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)-aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-{1-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)amino}ethylimidazole;

-   1-(1-Pentyl)-2-phenyl-5-(N-[indol-5-ylmethyl]-N-phenylmethyl)    aminomethylimidazole;

-   Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2,5-diphenyl-3H-imidazol-4ylmethyl)-amine

-   Benzo[1,3]dioxol-5-ylmethyl-benzyl-[3-butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]-amine

-   4-({Benzyl-[1′-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl]-amino}-methyl)-benzamide

-   4-{[Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-3-chloro-phenol

-   4-({[1-(3-Butyl-2-phenyl-3H-imidazol-4-yl)-pentyl]-cyclohexylmethyl-amino}-methyl)-phenol

-   4-{[Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-benzamide

-   1-(1-Propyl)-2-phenyl-5-(N-[indol-5-ylmethyl]-N-phenylmethyl)    aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[1-(S)-phenylethyl]-N-phenylmethyl)aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[1-(R)-phenylethyl]-N-phenylmethyl)aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4-dichlorophenyl]methyl)aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N,N-di[3,4-methylenedioxyphenylmethyl])    aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4-methoxyphenylmethyl])-aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[4-{1-propyl}phenylmethyl])    aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4-dichlorophenylethyl])    aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[4-nitrophenylmethyl])    aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[4-{1-propyloxy}phenylmethyl])aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[quinol-6-ylmethyl])-aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2,3-dichlorophenylmethyl])-aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4-dimethylphenylmethyl])-aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[indan-2-yl])-aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2-phenylethyl])amino-methylimidazole;

-   1-(1-Propyl)-2-phenyl-5-(N-[1,4-benzodioxan-6-ylmethyl]-N-phenylmethyl)aminomethyl-imidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)aminomethyl-imidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-ethyl)aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-propyl])aminomethyl-imidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl-N-[1-butyl])aminomethyl-imidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cycloheptylmethyl)amino-methylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-isobutyl)aminomethyl-imidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2-cyclopentylethyl])amino-methylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3-cyclopentylpropyl])amino-methylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[l    1-n-octyl])aminomethyl-imidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cyclopropylmethyl)amino-methylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cyclopentylmethyl)amino-methylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cyclohexylmethyl)amino-methylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[t-amyl])aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-{3-methyl}butyl)]amino-methylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-{2,2-dimethyl}butyl])    aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-methyl)aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2-thiophenylmethyl])amino-methylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[indol-5-ylmethyl])amino-methylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[{1-methylindol-5-yl}methyl])aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[4-hydroxy-2-chlorophenyl]-methyl)aminomethylimidazole;

-   1-(1-Butyl)-2-(3-fluorophenyl)-5-(1-[N-{2-chloro-4-hydroxyphenyl}methyl-N-phenylmethyl])    aminoethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[2,3-dihydrobenzo[b]furan-5-yl]methyl)aminomethylimidazole;

-   1-Butyl-2-(4-fluorophenyl)-5-(1-[N-{3,4-methylenedioxyphenyl}methyl-N-phenylmethyl]-amino)ethylimidazole;

-   1-(1-Butyl)-2-(2-thienyl)-5-(N-[3,4-methylenedioxyphenyl]methyl-N-phenylmethyl]aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4,5-trimethoxyphenylmethyl]-N-phenylmethyl)amino-methylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-phenylmethyl-N-[3,4-dimethoxyphenylmethyl])aminomethyl-imidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[4-dimethylaminophenylmethyl]-N-phenylmethyl)aminomethyl-imidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[4-methylaminophenylmethyl]-N-phenylmethyl)aminomethyl-imidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3-methyl-4-aminophenylmethyl]-N-phenylmethyl)aminomethyl-imidazole);

-   1-(1-Butyl)-2-phenyl-5-(N-[2,3-dichlorophenylmethyl]-N-phenylmethyl)aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-dichlorophenylmethyl]-N-phenylmethyl)aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3,4-difluorophenylmethyl]-N-phenylmethyl)aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-(benzo[b]thiophen-5-ylmethyl)-N-phenylmethyl)aminomethyl-imidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[4-ethoxyphenylmethyl]-N-phenylmethyl)aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-4-bromo-5-(N-phenylmethyl-N-[1-butyl])aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[4-methoxyphenylmethyl]-N-phenylmethyl)aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[6-chloro-3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)-aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[2,3-dichlorophenylmethyl]-N-[1-butyl])aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[3-methoxyphenylmethyl]-N-phenylmethyl)aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[2-chloro-4-fluorophenylmethyl]-N-phenylmethyl)aminomethyl-imidazole;

-   1-(1-Butyl)-2-phenyl-4-bromo-5-(N-[2,3-dichlorophenylmethyl]-N-[1-butyl])aminomethyl-imidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[2,6-dichlorophenylmethyl]-N-phenylmethyl)aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[2-chloro-4-hydroxyphenylmethyl]-N-phenylmethyl)aminomethyl-imidazole;

-   1-(1-Butyl)-2-phenyl-4-chloro-5-(N-phenylmethyl-N-[1-butyl])aminomethylimidazole;

-   4-{[Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-2-methyl-phenol

-   4-{[(3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-cyclohexylmethyl-amino]-methyl}-2-methyl-phenol

-   (3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-(2,6-difluoro-benzyl)-(4-methoxy-benzyl)-amine

-   Benzo[1,3]dioxol-5-ylmethyl-butyl-[3-butyl-2-(2-methoxy-phenyl)-5-phenyl-3H-imidazol-4-yl    methyl]-amine

-   4-({Benzyl-[3-butyl-2-(2-methoxy-phenyl)-5-phenyl-3H-imidazol-4-ylmethyl]-amino}-methyl)-benzenesulfonamide

-   Benzo[1,3]dioxol-5-ylmethyl-benzyl-[3-butyl-2-(2-methoxy-phenyl)-5-phenyl-3H-imidazol-4-yl    methyl]-amine

-   4-({Butyl-[3-butyl-2-(3-methoxy-phenyl)-5-phenyl-3H-imidazol-4-ylmethyl]-amino}methyl)-3-chloro-phenol

-   4-{[(3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-(4-methoxy-benzyl)-amino]-methyl}-benzoic    acid

-   4-({Benzyl-[3-butyl-2-(3-methoxy-phenyl)-5-phenyl-3H-imidazol-4-ylmethyl]-amino}-methyl)-3-chloro-phenol

-   Benzo[1,3]dioxol-5-ylmethyl-benzyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-pentyl]-amine

-   Benzo[1,3]dioxol-5-ylmethyl-benzyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl-ethyl]-amine

-   4-{[Butyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-benzamide

-   Benzo[1,3]dioxol-5-ylmethyl-benzyl-[3-butyl-5-(4-fluoro-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]amine

-   3-{[Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-phenol

-   4-{[Butyl-(3-butyl-5-tert-butyl-2-phenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-benzamide

-   Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-(2,3    dihydro-benzo[1,4]dioxin-6-ylmethyl)-amine

-   (3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-(2,5-difluoro-benzyl)-(4-methoxy-benzyl)-amine

-   (3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-(2,6-dichloro-benzyl)-(4-methoxy-benzyl)-amine

-   4-{[Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-2,6-dimethyl-phenol

-   4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]-cyclohexylmethyl-amino}-methyl)-2,6-dimethyl-phenol

-   [3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]-cyclohexylmethyl-(2,3-dihydro-benzo    furan-5-ylmethyl)-amine

-   4-{[Butyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-2,6-dimethyl-phenol

-   4-({Butyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl]-amino}-methyl)-2,6-dimethyl-phenol

-   4-{[(3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-(4-dimethylamino-benzyl)-amino]-methyl}-benzoic    acid

-   4-{5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino)-methyl]-2,4-diphenyl-imidazol-1-yl}-butyric    acid ethyl ester

-   4-{5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino)-methyl]-2,4-diphenyl-imidazol-1-yl}-butan-1-ol

-   (4-{[(3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-cyclohexylmethyl-amino]-methyl}-phenyl)-dimethyl-amine

-   1-(1-Butyl)-2-phenyl-5-(N-[4-{1-pyrrolidinyl}phenylmethyl]-N-phenylmethyl)aminomethyl-imidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[4-diethylaminophenylmethyl]-N-phenylmethyl)aminomethyl-imidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[pyridin-2-ylmethyl]-N-phenylmethyl)aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[pyridin-3-ylmethyl]-N-phenylmethyl)aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[pyridin-4-ylmethyl]-N-phenylmethyl)aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[2-fluoro-6-chlorophenylmethyl]-N-phenylmethyl)aminomethyl-imidazole);

-   1-(1-Butyl)-2-phenyl-5-(N-[2,4-dichlorophenylmethyl]-N-phenylmethyl)aminomethyl-imidazole);

-   1-(1-Butyl)-2-phenyl-5-(N-[4-chlorophenylmethyl]-N-phenylmethyl)aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[4-hydroxyphenylmethyl]-N-phenylmethyl)aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[4-trifluoromethoxyphenylmethyl]-N-phenylmethyl)aminomethyl-imidazole);

-   1-(1-Butyl)-2-phenyl-5-(N-[2-chloro-3,4-dimethoxyphenylmethyl]-N-phenylmethyl)amino-methylimidazole);

-   1-(1-Butyl)-2-phenyl-5-(N-[4-nitrophenylmethyl]-N-phenylmethyl)aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[4-aminophenylmethyl]-N-phenylmethyl)aminomethylimidazole;

-   1-(1-Butyl)-2,4-diphenyl-5-(N-phenylmethyl-N-[1-butyl])aminomethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[2-aminopyridin-5-ylmethyl]-N-phenylmethyl)aminomethyl-imidazole

-   1-(1-Butyl)-2-phenyl-5-(N-[2,3-dihydrobenzo[b]furan-5-ylmethyl]-N-phenylmethyl)amino-methylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[2-chloro-4-hydroxyphenylmethyl]-N-[1-butyl])aminomethyl-imidazole)

-   1-(1-Butyl)-2-phenyl-4-methyl-5-(N-phenylmethyl-N-[1-butyl])aminomethylimidazole;

-   1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[2-chloro-4-hydroxyphenylmethyl]-N-phenylmethyl)-aminomethylimidazole;

-   1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-[2-chloro-4-hydroxyphenylmethyl]-N-phenylmethyl)-aminomethylimidazole;

-   1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-[2,3-dichlorophenylmethyl]-N-phenylmethyl)aminomethylimidazole;

-   1-(1-Butyl)-2-(3-fluorophenyl)-(N-[4-dimethylaminophenylmethyl]-N-phenylmethyl)amino-methylimidazole;

-   1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-[4-{1-pyrrolidinyl}phenylmethyl]-N-phenylmethyl)amino-methylimidazole;

-   1-(1-Butyl)-2-(3-chlorophenyl)-5-(1-[N-{2-chloro-4-hydroxyphenylmethyl}-N-phenylmethyl]amino)ethylimidazole;

-   1-(1-Butyl)-2-phenyl-5-(N-[indol-5-ylmethyl]-N-phenylmethyl)aminomethylimidazole;

-   1-(1-Butyl)-2-(4-fluorophenyl)-5-(1-N,N-di[3,4-methylenedioxyphenylmethyl]amino)ethylimidazole;

-   2-{[5-({Butyl[(1-butyl-2,4-diphenylimidazol-5-yl)methyl]amino}methyl)-2-pyridyl]amino}ethan-1-ol;

As discussed above, preferred compounds of the invention exhibit goodactivity in standard in vitro C5 receptor mediated chemotaxis assay,specifically the assay as specified in Example 12, which follows.References herein to “standard in vitro C5 receptor mediated chemotaxisassay” are intended to refer to that protocol as defined in Example 12which follows. Preferred compound of the invention exhibit an EC₅₀ ofabout 100 μM or less in such a standard C5a mediated chemotaxis assay,more preferably an EC₅₀ of about 10 μM or less in such a standard C5amediated chemotaxis assay, still more preferably an EC₅₀ of about 1 μMin such a standard C5a mediated chemotaxis assay, even more preferablyan EC₅₀ of about 0.1 μM in such a standard C5a mediated chemotaxisassay.

Additional assays suitable for determining the effects of small moleculecompounds on C5a receptor binding and receptor modulatory activity, aswell as assays suitable for measuring their effects on C5a-inducedneutropenia in vivo, can be found in the published literature, forexample in U.S. Pat. No. 5,807,824, which is incorporated herein byreference for its disclosure in this regard in Examples 6–9, columns19–23, as well as for its discussion of complement and inflammation atcolumns 1–2. Those of skill in the art will recognize that such assayscan be readily adapted to the use of cells or animals of differentspecies as deemed appropriate.

In one aspect of the invention, one or more compounds of the invention,preferably in solution in a pharmaceutically acceptable carrier as apharmaceutical preparation, is used to perfuse a donor organ prior totransplantation of the organ into a recipient patient. Such perfusion ispreferably carried out using a solution comprising an concentration ofthe compound of the invention that is an effective amount sufficient toinhibit C5a mediated effects in vitro or in vivo. Such perfusionpreferably reduces the severity or frequency of one or more of theinflammatory sequelae following organ transplantation when compared tothat occurring in control (including, without restriction, historicalcontrol) transplant recipients who have received transplants of donororgans that have not been so perfused.

Definitions

In certain situations, the compounds of the invention may contain one ormore asymmetric elements such as stereogenic centers, stereogenic axesand the like, e.g. asymmetric carbon atoms, so that the compounds canexist in different stereoisomeric forms. These compounds can be, forexample, racemates or optically active forms. For compounds with two ormore asymmetric elements, these compounds can additionally be mixturesof diastereomers. In these situations, the single enantiomers, i.e.,optically active forms, can be obtained by asymmetric synthesis,synthesis from optically pure precursors or by resolution of theracemates. Resolution of the racemates can be accomplished, for example,by conventional methods such as crystallization in the presence of aresolving agent, or chromatography, using, for example a chiral HPLCcolumn.

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valence isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., =0), then 2 hydrogens on the atom arereplaced. Keto substituents are not present on aromatic moieties. Thepresent invention is intended to include all isotopes of atoms occurringin the present compounds. Isotopes include those atoms having the sameatomic number but different mass numbers. By way of general example, andwithout limitation, isotopes of hydrogen include tritium and deuteriumand isotopes of carbon include ¹¹C, ¹³C, and ¹⁴C.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0–2 R*, then said group mayoptionally be substituted with up to two R* groups and R* at eachoccurrence is selected independently from the definition of R*. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

As indicated herein, various substituents of the compounds of thepresent invention and various formulae set forth herein are “optionallysubstituted”, including, e.g., Ar₁, Ar₂, R, R₁, R₂, R₃, R_(3A), R₄, R₅,R₆, R₇, R_(A), R_(A)′, R_(B), and R_(C). When substituted, thosesubstituents may be substituted at one or more of any of the availablepositions, typically 1, 2, 3, or 4 positions, by one or more suitablegroups such as those disclosed herein.

Suitable groups or “substituted” moities of compounds of the inventioninclude e.g., halogen such as fluoro, chloro, bromo or iodo; cyano;hydroxyl; nitro; azido; alkanoyl such as a C₁₋₆ alkanoyl group such asacyl and the like; carboxamido; alkyl groups including those groupshaving 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5, or 6 carbon atoms;alkenyl and alkynyl groups including groups having one or moreunsaturated linkages and from 2 to about 12 carbon, or 2, 3, 4, 5 or 6carbon atoms; alkoxy groups having those having one or more oxygenlinkages and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5 or 6carbon atoms; aryloxy such as phenoxy; alkylthio groups including thosemoieties having one or more thioether linkages and from 1 to about 12carbon atoms, or 1, 2, 3, 4, 5 or 6 carbon atoms; alkylsulfinyl groupsincluding those moieties having one or more sulfinyl linkages and from 1to about 12 carbon atoms, or 1, 2, 3, 4, 5, or 6 carbon atoms;alkylsulfonyl groups including those moieties having one or moresulfonyl linkages and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5,or 6 carbon atoms; aminoalkyl groups such as groups having one or more Natoms and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5 or 6 carbonatoms; carbocyclic aryl having 6 or more carbons, particularly phenyl(e.g. an Ar group being a substituted or unsubstituted biphenyl moiety);arylalkyl having 1 to 3 separate or fused rings and from 6 to about 18carbon ring atoms, with benzyl being a preferred group; aralkoxy having1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms,with O-benzyl being a preferred group; or a heteroaromatic orheteroalicyclic group having 1 to 3 separate or fused rings with 3 toabout 8 members per ring and one or more N, O or S atoms, e.g.coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl,thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl,benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl,morpholino and pyrrolidinyl.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, having thespecified number of carbon atoms. Examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, 1-propyl, n-butyl, s-butyl,t-butyl, n-pentyl, and s-pentyl. Preferred alkyl groups are C₁–C₈ andC₁₋₆ alkyl groups. Especially preferred alkyl groups are methyl, ethyl,propyl, butyl, 3-pentyl. The term C₁₋₆ alkyl as used herein includesalkyl groups consisting of 1 to 6 carbon atoms, which may contain acyclopropyl moiety. Suitable examples are methyl or ethyl.

“Cycloalkyl” is intended to include saturated ring groups, having thespecified number of carbon atoms, such as cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl and bridged or caged saturated ring groupssuch as norbornane or adamantane and the like.

In the term “(C₃₋₆ cycloalkyl)C₁₋₄ alkyl”, as defined above, the pointof attachment is on the alkyl group. This term encompasses, but is notlimited to, cyclopropylmethyl, cyclohexylmethyl and cyclohexylethyl.

“Alkenyl” is intended to include hydrocarbon chains of either a straightor branched configuration comprising one or more unsaturatedcarbon—carbon bonds, which may occur in any stable point along thechain, such as ethenyl and propenyl.

“Alkynyl” is intended to include hydrocarbon chains of either a straightor branched configuration comprising one or more triple carbon—carbonbonds that may occur in any stable point along the chain, such asethynyl and propynyl.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogen (for example—C_(v)(X^(i))_(wi)(H_(2v+1−Σ(wi))) where v=1 to 3; X^(i)=F(i=1),Cl(i=2), Br(i=3), I(i=4) and Σw_(i)≦2v+1). Examples of haloalkylinclude, but are not limited to, trifluoromethyl, trichloromethyl,pentafluoroethyl, and pentachloroethyl.

“Alkoxy” represents an alkyl group as defined above with the indicatednumber of carbon atoms attached through an oxygen bridge. Examples ofalkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy,1-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy,3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and3-methylpentoxy.

As used herein, the term “carbocyclic aryl” indicates aromatic groupscontaining only carbon in the aromatic ring. Such aromatic groups may befurther substituted with carbon or non-carbon atoms or groups. Typicalcarbocyclic aryl groups contain 1 to 3 separate of fused rings and from6 to about 18 ring atoms, without heteroatoms as ring members.Specifically preferred carbocyclic aryl groups include phenyl, napthyl,including 1-naphthyl and 2-naphthyl, and acenaphthyl.

By the term “energetically accessible conformer” is meant any conformerof a compound that falls within about a 15 Kcal/mol window above thelowest energy conformation (as for example that found in a monte carloor systematic confirmational search) by using MM2, MM3, or MMFF forcefields as implemented in molecular modeling software such as MacroModel®v 7.0, Schrödinger, Inc., Portland, Oreg. United States and Jersey City,N.J., United States, http://www.schrodinger.com or the like.

Peptidomimetic compounds are generally compounds with “chemicalstructures derived from bioactive peptides which imitate naturalmolecules” (Murray Goodman and Seonggu Ro, “Peptidomimetics for DrugDesign” chapter twenty in Burger's Medicinal Chemistry and DrugDiscovery, Volume 1: Principles and Practice, Manfred E. Wolff, ed. JohnWiley & Sons, Inc., NY, 1995, pp. 801–861.) As used herein and in theclaims, the term peptidomimetic additionally comprises peptoidcompounds, which are compounds that comprise oligomers of N-substitutednatural amino acids, and the term further comprises any compound havingmore than two amide bonds.

As used herein, the terms “heteroaryl” and “heteroalicyclic” group areintended to indicate a stable 5-to 7-membered monocyclic or bicyclic or7-to 10-membered bicyclic heterocyclic ring which is saturated,partially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and from 1 to 4 heteroatoms independently selected from thegroup consisting of N, O and S and including any bicyclic group in whichany of the above-defined heterocyclic rings is fused to a benzene ring.The term heteroaryl indicates that the group contains at least 1aromatic ring. The nitrogen and sulfur heteroatoms may optionally beoxidized. The heterocyclic ring may be attached to its pendant group atany heteroatom or carbon atom that results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. A nitrogen in theheterocycle may optionally be quaternized.

It is preferred that when the total number of S and O atoms in theheterocycle exceeds 1, then these heteroatoms are not adjacent to oneanother. It is preferred that the total number of S and O atoms in theheterocycle is not more than 1, 2, or 3, more typically 1 or 2. It ispreferred that the total number of S and O atoms in the aromaticheterocycle is not more than 1.

Examples of heteroaryl groups and other heterocycles include, but arenot limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl,benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,benzthiazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl,phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl,thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

Preferred heteroaryl groups include, but are not limited to, pyridinyl,pyrimidinyl, furanyl, and thienyl. Also included are fused ring andspiro compounds containing, for example, the above heterocycles.

The term “halogen” indicates fluorine, chlorine, bromine, or iodine.

The term “pharmaceutically acceptable salts” includes, but is notlimited to non-toxic salts with inorganic acids such as hydrochloride,sulfate, phosphate, diphosphate, hydrobromide, and nitrite or salts withan organic acids such as malate, maleate, fumarate, tartrate, succinate,citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate,2-hydroxyethylsulfonate, salicylate and stearate. Similarly,pharmaceutically acceptable cations include, but are not limited tosodium, potassium, calcium, aluminum, lithium and ammonium. The presentinvention also encompasses the prodrugs of the compounds disclosed.

Examples of bicyclic oxygen containing groups of the formula:

(R_(A) may also be indicated R_(B)) include the following:

Methods of Treating Patients

The present invention provides methods of treating patients sufferingfrom diseases or disorders involving pathologic activation of C5areceptors. Such diseases and disorders may include the following.

Such disorders that may be autoimmune in nature and are suitable fortreatment in accordance with the present invention include e.g.rheumatoid arthritis, systemic lupus erythematosus (and associatedglomerulonephritis), psoriasis, Crohn's disease, vasculitis, irritablebowel syndrome, dermatomyositis, multiple sclerosis, bronchial asthma,pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmunehemolytic and thrombocytopenic states, Goodpasture's syndrome (andassociated glomerulonephritis and pulmonary hemorrhage), andimmunovasculitis. Such inflammatory and related conditions includeneutropenia, sepsis, septic shock, Alzheimer's disease, stroke,inflammation associated with severe burns, lung injury, myocardialinfarction, coronary thrombosis, vascular occlusion, post-surgicalvascular reocclusion, artherosclerosis, traumatic central nervous systeminjury and ischemic heart disease, and ischemia-reperfusion injury, aswell as acute (adult) respiratory distress syndrome (ARDS), systemicinflammatory response syndrome (SIRS), multiple organ dysfunctionsyndrome (MODS), tissue graft rejection, and hyperacute rejection oftransplanted organs. Also included are pathologic sequellae associatedwith insulin-dependent diabetes mellitus (including diabeticretinopathy), lupus nephropathy, Heyman nephritis, membranous nephritisand other forms of glomerulonephritis, contact sensitivity responses,and inflammation resulting from contact of blood with artificialsurfaces that can cause complement activation, as occurs, for example,during extracorporeal circulation of blood (e.g., during hemodialysis orvia a heart-lung machine, for example, in association with vascularsurgery such as coronary artery bypass grafting or heart valvereplacement) such as extracorporeal post-dialysis syndrome, or inassociation with contact with other artificial vessel or containersurfaces (e.g., ventricular assist devices, artificial heart machines,transfusion tubing, blood storage bags, plasmapheresis,plateletpheresis, and the like).

Treatment methods of the invention include in general administration toa patient a therapeutically effective amount of one or more compounds ofthe invention. Suitable patients include those subjects suffering fromor susceptible to (i.e. propylactic treatment) a disorder or diseaseidentified herein. Typical patients for treatment in accordance with theinvention include mammals, particularly primates, especially humans.Other suitable subjects include domesticated companion animals such as adog, cat, horse, and the like, or a livestock animal such as cattle,pig, sheep and the like.

Pharmaceutical Preparations

The compounds of the invention may be administered orally, topically,parenterally, by inhalation or spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. Oral administration in theform of a pill, capsule, elixir, syrup, lozenge, troche, or the like isparticularly preferred. The term parenteral as used herein includesinjections and the like, such as subcutaneous, intradermal,intravascular (e.g., intravenous), intramuscular, intrasternal, spinal,intrathecal, and like injection or infusion techniques, withsubcutaneous, intramuscular and intravascular injections or infusionsbeing preferred. In addition, there is provided a pharmaceuticalformulation comprising a compound of the invention and apharmaceutically acceptable carrier. One or more compounds of theinvention may be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvantsand if desired other active ingredients. The pharmaceutical compositionscontaining compounds of the invention may be in a form suitable for oraluse, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsion, hard or softcapsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylceullulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono-or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the invention may also be administered in the form ofsuppositories e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of the invention may be administered parenterally, preferablyin a sterile non-toxic, pyrogen-free medium. The drug, depending on thevehicle and concentration used, can either be suspended or dissolved inthe vehicle. Advantageously, adjuvants such as local anesthetics,preservatives and buffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment orpreventions of conditions involving pathogenic C5a activity,particularly those disorders list in the “background of the invention”section (about 0.5 mg to about 7 g per patient per day). The amount ofactive ingredient that may be combined with the carrier materials toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. Dosage unit forms willgenerally contain between from about 1 mg to about 500 mg of an activeingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most disorders, adosage regimen of 4 times daily, three times daily, or less ispreferred, with a dosage regimen of once daily or 2 times daily beingparticularly preferred.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination (i.e., otherdrugs being administered to the patient), the severity of the particulardisease undergoing therapy, and other factors, including the judgment ofthe prescribing medical practitioner.

Preferred compounds of the invention will have favorable pharmacologicalproperties. Such properties include, but are not limited tobioavailability (e.g., oral bioavailibilty, preferably high enough topermit oral administration of doses of less than 2 grams, preferably ofless than or equal to one gram), low toxicity, low serum protein bindingand desirable in vitro and in vivo half-lifes. Distribution in the bodyto sites of complement activity is also desirable, e.g., compounds usedto treat CNS disorders will preferably penetrate the blood brainbarrier, while low brain levels of compounds used to treat peripheraldisorders are typically preferred.

Assays may be used to predict these desirable pharmacologicalproperties. Assays used to predict bioavailability include transportacross human intestinal cell monolayers, including Caco-2 cellmonolayers. Toxicity to cultured hepatocycles may be used to predictcompound toxicity. Penetration of the blood brain barrier of a compoundin humans may be predicted from the brain levels of the compound inlaboratory animals given the compound intravenously.

Serum protein binding may be predicted from albumin binding assays. Suchassays are described in a review by Oravcová, et al. (Journal ofChromatography B (1996) volume 677, pages 1–27).

Compound half-life is inversely proportional to the frequency of dosagerequired for the effective administration of a compound. In vivohalf-lifes of compounds may be predicted, e.g., from assays ofmicrosomal half-life as described by Kuhnz and Gieschen (Drug Metabolismand Disposition, (1998) volume 26, pages 1120–1127).

Preparation of compounds

Representative methods for preparing the compounds of the invention areshown in the following Schemes. Schemes 1 and 2 show the preparation ofarylimidazole compounds. Scheme 1 illustrates the preparation ofarylimidazole compounds where R₁ is hydrogen or halogen. Scheme 2represents of the preparation of aryl imidazole compounds where R₁ isalkyl. Within Schemes 1 and 2 the variables Ar₁, Ar₂, R₁, R₂, R₃ andR₄˜are defined as above for Formula I.

As shown in Scheme 1, an appropriately substituted arylnitrile 10 isconverted to the imidate 11 via treatment with hydrogen chloride gas inmethanol followed by subsequent treatment with base to release the freebase. Amidine 12 is prepared from 11 by treatment with a primary amine.2-Arylimidazole-4-carboxaldehyde 13 is prepared from 12 by one ofseveral methods described in the chemical literature, for instance, bytreatment with 2-bromo-3-isopropoxyacrolein in the presence of base.See, for example, J. Org, Chem., 62: 8449 (Shilcrat et al., 1997).

Aldehyde 13 can then be transformed into hydroxymethylimidazole 14either by reduction (for cases where R₄ is hydrogen) or by treatmentwith the appropriate organometallic (for cases where R₄ is C₁–C₆ alkyl).The hydroxy group of 14 is converted to either a halogen or sulfonateester leaving group. Treatment of this intermediate with an appropriatesecondary amine in the presence of base provides2-aryl-4-aminomethylimidazole 15. Alternatively, the aminoalkylfunctionality of 15 may be elaborated by sequentialamination-acylation-reduction steps. In situations where R₁ is ahalogen, it may be prepared from 15 (R₁=H) by treatment with themolecular halogen, a halosuccinimide or the like.

As shown in Scheme 2, an appropriately substituted2-aryl-4-substitutedimidazole 20 can be N-alkylated by treatment withbase such as sodium hydride and an alkyl halide or alkylsulfonate esterto provide the trisubstituted imidazole 21. Hydroxymethylation of 21under the conditions of the Mannich reaction provideshydroxymethylimidazole 22. In examples where R₃ is alkyl, hydroxymethylderivative 24 is prepared from 22 by oxidation to aldehyde 23 andsubsequent treatment with an appropriate organometallic reagent such asan alkyl lithium or Grignard reagent. Conversion of 22 or 24 to thedesired 2-aryl-5-aminomethylimidazoles is carried out by conversion ofthe hydroxymethyl to a halogen or sulfonate ester leaving group followedby treatment with a secondary amine. Alternatively, the aminoalkylfunctionality of the 2-aryl-5-aminomethylimidazole product may beelaborated by sequential amination-acylation-reduction steps.

The 2-aryl-4-substitutedimidazole 20 may be prepared by methodsdescribed in the chemical literature, for instance, via condensation ofan arylamidine with a halomethyl or hydroxymethyl ketone.

Cycloalkylimidazoles

An illustration of the preparation of compounds of theCycloalkylimidazole compounds of the present invention is given inScheme 3. Within Scheme 3 the variables n, Ar₁, Ar₂, R₂, R₃, R_(3a), R₄,RS, R₆, R_(5a), R_(6a), R₇ and X are defined previously.

As shown in Scheme 3, an appropriately substituted arylamidine 30 iscondensed with an appropriately substituted 2-halo-3-alkoxyenone 31 toprovide a 2-aryl-4,5-cycloalkylimidazole 32. The ketone functionality of32 can be either reduced (R₇═H) or treated with an appropriateorganometallic (for cases where R₇ is alkyl) to give the cyclic alcohol33. Compounds of general formula 34 can be prepared from 33 by one ofseveral methods described in the chemical literature, for instance, bytreatment with thionyl chloride or by treatment with an alkyl orarylsulphonyl chloride in the presence of base.

Compounds of formula 34 can then be transformed into compounds ofgeneral Formula 35 by direct treatment with the appropriate secondaryamine. Alternatively, the X functionality of 34 may be transformed intoa tertiary amine in a stepwise manner. In this case, 34 would be treatedwith a primary amine to provide an intermediate secondary amine. This,in turn, could be alkylated to give cycloalkylimidazole compounds of theinvention.

Pyridines

An illustration of the preparation of pyridine compounds of the presentinvention is given in Scheme 4. Those having skill in the art willrecognize that the starting materials may be varied and additional stepsemployed to produce compounds encompassed by the present invention.Within Scheme 4 the variables Ar₁, Ar₂, R, R₁, R₂, R₃, and R₄ aredefined as previously described.

As shown in Scheme 4, an appropriately substituted 4-phenyloxazole 40 iscondensed with an appropriately substituted maleic acid to provide a2-phenylisonicotinic acid 41. The carboxylic acid functionality of 41can be reduced directly to the primary alcohol (43, R₃=H) or convertedby methods known to the art to an intermediate aldehyde 42 andsubsequently treated with the appropriate organometallic (for caseswhere R₃ is alkyl) to give a secondary alcohol 43. Compounds of generalformula 44 can be prepared from 43 by one of several methods describedin the chemical literature, for instance, by initial treatment withthionyl chloride or with an alkyl or arylsulphonyl chloride in thepresence of base, followed by subsequent condensation with a primaryamine. Compounds of formula 44 can then be transformed into compounds offormula 45 by direct treatment with the appropriate alkylating agent or,alternatively, by reductive alkylation. Alternatively, the tertiaryamine functionality of formula 45 may be realized directly fromcompounds of formula 43 by initial treatment with thionyl chloride orwith an alkyl or arylsulphonyl chloride in the presence of base,followed by subsequent condensation with a secondary amine.

Pyrazoles

An illustration of the preparation of arylpyrazole compounds of thepresent invention is given in Scheme 5. Within Scheme 5 the variablesAr₁, Ar₂, R₁, R₂, R₃, and R₄ are defined as previously described.

As shown in Scheme 5, an appropriately substituted phenylhydrazineadduct 50 is condensed with an appropriately substituted α-ketoester 51,in the presence of a Lewis acid, preferably ZnCl₂, with heating at50–200° C., preferably at 125° C. to provide a 1-phenylpyrazole ester52. The carboxylic acid functionality of 52 can be reduced directly tothe primary alcohol (53, R₃=H) or converted by methods known to the artto an intermediate aldehyde and subsequently treated with theappropriate the appropriate organometallic (for cases where R₃ is alkyl)to give a secondary alcohol 53. Compounds of general formula 54, whereLG represents a leaving group, can be prepared from 53 by one of severalmethods described in the chemical literature, for instance, by initialtreatment with thionyl chloride or with an alkyl or arylsulphonylchloride in the presence of base, followed by subsequent condensationwith a primary amine. Compounds of formula 54 can then be transformedinto compounds of formula 58 by sequential treatment with theappropriate primary amine followed by direct alkylation or reductivealkylation of the intermediate secondary amine. Alternatively, thetertiary amine functionality of formula 58 may be realized directly fromcompounds of formula 53 by initial treatment with thionyl chloride orwith an alkyl or arylsulphonyl chloride in the presence of base,followed by subsequent condensation with a secondary amine.

An alternative route to the preparation of compounds of Formula 58 fromthe 1-phenylpyrazole ester 52 may be realized by hydrolysis of 52 to acarboxylic acid of general structure 56, followed by amide formation toprovide 57 and, finally, reduction of the amide functionality to thetertiary amine of 58 (R₃=H).

Scheme 6. Preparation of 2-(1-aryl-1,2,3,4-tetrahydroiso quinolin-2-yl)acetamides and bicyclics of other ring sizes (n=0, 1, 2, 3, etc)

The 2-(1,2,3,4-tetrahydroisoquinolin-2-yl) acetamides of general formula62 of the present invention may be prepared according to the proceduredescribed graphically in Scheme 6, wherein a compound of general Formula60, prepared according to literature procedures, (for example: Scully,Frank E., Jr.; Schlager, John J. Synthesis of dihydroisoquinolines and1-substituted tetrahydroisoquinolines. Heterocycles (1982), 19(4), 653–6or Shinohara, Tatsumi; Takeda, Akira; Toda, Jun; Terasawa, Noriyo; Sano,Takehiro. A highly efficient synthesis of 1-methyl-, 1-benzyl-, and1-phenyl-1,2,3,4-tetrahydroisoquinolines by a modified Pummererreaction. Heterocycles (1997), 46: 555–566.) is combined (in anappropriate solvent in the presence of an organic or inorganic base)with an appropriately substituted acetamide derivative possessing aleaving group X at its 2 position. For example, X may be halogen, alkylor aryl sulfonate, or polyfluoroalkylsulfonate. Acetamides of generalFormula 61 may be prepared via condensation of the appropriate secondaryamine with a 2-haloacetylhalide (such as 2-chloroacaetyl chloride) inthe presence of base. Alternatively acetamides of general formula 61 canbe prepared by condensation of the appropriate secondary amine witheither a 2-(alkylsulfonylester)acetic acid or2-(arylsulfonylester)acetic acid in the presence of an coupling agentsuch as CDI or the like.

Within Scheme 6, R₁, R₂, R₃, R₄ and R₅ may be the same or different andare chosen from hydrogen, halogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, hydroxy,trifluoromethyl, trifluoromethoxyl, cyano, nitro, hydroxy carbonyl(COOH), aminocarbonyl (CONH₂), mono or dialkylaminocarbonyl,sulfonamido, mono or dialkylsulfonamido, amino, mono- or di-alkylamino,aceto, acetoxy or 3,4-methylenedioxy or ethylenedioxy. The term n refersto an integer from 1 to 3. R₆ may be C₁–C₉ straight or branched chainalkyl, benzyl (substituted or unsubstituted), phenylethyl (substitutedor unsubstituted), phenylpropyl (substituted or unsubstituted), or maybe cycloalkyl fused with an aromatic group such as1,2,3,4-tetrahydronaphthyl, 1- or 2-indanyl or suberanyl.

Scheme 7. Preparation of Ortho Biarylamides

The preparation of the ortho biarylamides of the present invention maybe carried out via a series of chemical transformations similar to thosedisplayed graphically in Scheme 7. An individual skilled in the art mayfind modifications of one or several of the synthetic steps describedherein without diverting significantly from the overall syntheticscheme.

Thus, as shown, the synthetic route begins with a benzoic acid ofgeneral structure 70 possessing a group X at the ortho position. This Xgroup may be iodine, bromine, chlorine, sulfonate ester orpolyfluoroalkylsulfonate ester. The benzoic acid may also be substitutedby up to four independently chosen substitutents represented by thevariables R₁–R₄. Examples of suitable substituents include hydrogen,chlorine, fluorine, cyano, C₁–C₆ straight or branched chain alkyl, C₁–C₆straight or branched chain alkoxy, trifluoromethyl, trifluoromethoxy,nitro, amino, mono or dialkyl amino, sulfonamido, mono ordialkylsulfonamido, alkylthio e.g. methylthio, alkylsulfoxide,alkylsulfone, acetyl, acetoxy, alkoxycarbonyl (COOAlkyl) ordialkylaminocarbonyl (CON[alkyl]₂). Additionally, two adjacent groups(i.e. R₁ and R₂, or R₂ and R₃ or R₃ and R₄) may be taken together with achain of from 3 to 5 methylene carbons to form a alkyl ring of from fiveto seven carbons fused to the benzoic acid moiety. Additionally, twoadjacent groups (i.e R₁ and R₂, or R₂ and R₃ or R₃ and R₄) may be takentogether with an alkyloxy chain, for example OCH₂O or OCH₂CH₂O to forman oxygen-containing moiety (in this example methylenedioxy orethylenedioxy, respectively) fused to the benzoic acid.

This benzoic acid is then activated by conversion to an acid chloridewith thionyl chloride, oxalyl chloride or the like. Alternatively, itmay be activated by treatment with carbonyldiimidazole or a similaragent. The activated benzoic acid is then treated with an appropriatesecondary amine in the presence of base to provide a tertiary amide ofgeneral structure 71.

Amide 71 is then converted to the biaryl structure 72 through the use ofaryl coupling reactions know in the chemical literature. Examples ofsuch reactions are the Stille reaction where an aryl trialkyltin reagentis coupled to an appropriate aryl in the presence of a catalyst such aspalladium or nickel; or a Suzuki reaction where a arylboronic acid iscoupled to an appropriate aryl in the presence of a nickel or palladiumcatalyst in the presence of base.

The group “Ar” of General structure 72 may be a phenyl which may besubstituted with up to five additional independently chosensubstitutents, e.g. hydrogen, halogen, cyano, C₁–C₆ straight or branchedchain alkyl, C₁–C₆ straight or branched chain alkoxy, trifluoromethyl,trifluoromethoxy, nitro, amino, mono or dialkyl amino, sulfonamido, monoor dialkylsulfonamido, alkylthio e.g. methylthio, alkylsulfoxide,alkylsulfone, acetyl, acetoxy, hydroxycarbonyl (COOH), alkoxycarbonyl(COOAlkyl), aminocarbonyl (CONH₂), monoalkylaminocarbonyl,dialkylaminocarbonyl (CON[alkyl]₂, methylenedioxy or ethylenedioxy.

The Ar of General Structure 72 may also represent a heteroaryl groupsuch as 1- or 2-thienyl or 1- or 2-furanyl. Such a heteroaryl groupwhich may be additionally substituted by up to three independentlychosen substituents, such as hydrogen, halogen, cyano, C₁–C₆ straight orbranched chain alkyl, C₁–C₆ straight or branched chain alkoxy,trifluoromethyl, trifluoromethoxy, dialkyl amino, sulfonamido, mono ordialkylsulfonamido, alkylthio e.g. methylthio, alkylsulfoxide,alkylsulfone, acetyl, acetoxy, hydroxycarbonyl (COOH), alkoxycarbonyl(COOAlkyl), aminocarbonyl (CONH₂), monoalkylcarbonyl,dialkylaminocarbonyl (CON[alkyl]₂.

Scheme 8. General Preparation of Azaaryl benzamides

The preparation of 2-imidazolyl, 2-pyrrazolyl and 2-(1,2,4)-triazolylbenzamides begins with an appropriately substituted benzonitrilederivative having a leaving group X at the position ortho to thecarboxylic acid functionality. Most commonly this group would be afluorine or chlorine group. This benzonitrile may be optionallysubstituted or additionally substituted by up to four substituents(R₁–R₄) which may be the same or different (examples of suchsubstituents are: hydrogen, halogen, cyano, C₁–C₆ straight or branchedchain alkyl, C₁–C₆ straight or branched chain alkoxy, trifluoromethyl,trifluoromethoxy, nitro, amino, mono or dialkyl amino, sulfonamido, monoor dialkylsulfonamido, methylthio, alkylsulfoxide, alkylsulfone, acetyl,acetoxy, alkoxycarbonyl (COOAlkyl) or dialkylaminocarbonyl(CON[alkyl]₂).

The benzonitrile 73 is mixed with the azaheterocycle 74 (wherein A and Bmay be either nitrogen or carbon with the caveat that both A and B notbe carbon. R₅ and R₆ may be the same as those groups described forR₁–R₄.) This condensation may be carried out either in a single phasesystem in an appropriate solvent and base, or in a two-phase mannerusing a phase transfer catalyst.

2-Azaheterocyclicbenzonitrile 75 is the hydrolyzed to the correspondingbenzoic acid 76 via means common to the chemical literature, forinstance mineral acid.

The benzoic acid 76 is then activated via thionyl chloride, CDI or othermeans known to the chemical literature and condensed with anappropriately substituted secondary amine to provide the desired finalproducts 77.

EXAMPLES

The general methods given in Schemes 1 to 8 above for the preparation ofcompounds of the present invention are further illustrated by thefollowing examples. Specifically, the methods given in Schemes 1 and 2for the preparation of aryl imidazoles are illustrated by Examples 1–4,shown below. An example of the method shown in Scheme 3 for thepreparation of cycloalkylimidazoles is given in example 5, and exampleof the method shown in Scheme 4 for the preparation of arylpyridines isgiven in example 6, and an example of the method shown in Scheme 5 forthe preparation of arylpyrazoles is given in example 7. The method shownby Scheme 6 for the preparations of2-(1-Aryl-1,2,3,4-tetrahydroisoquinolin-2-yl)acetamides is furtherillustrated in example 8. The methods shown in Schemes 7 and 8 for thepreparation of ortho biarylamides and azaarylamides, respectively, areexemplified in Examples 9 and 10. Unless otherwise specified allstarting materials and reagents are of standard commercial grade, andare used without further purification, or are readily prepared from suchmaterials by routine methods. Those skilled in the art of organicsynthesis will recognize that starting materials and reaction conditionsmay be varied to achieve the desired end product.

Example 1 Preparation of an arylimidazole compound:1-(1-butyl)-2-phenyl-5-(N,N-di[3,4-methylenedioxyphenylmethyl])aminomethylimidazole (Compound 106)

N-(n-butyl)-benzamidine (101). To a solution of methyl benzimidatehydrochloride (12 g, 0.07 mole) in dimethylformamide (DMF, 20 mL) isadded 7 ml of triethylamine at 0° C. After 2 h the reaction is filteredto remove triethylamine hydrochloride. To the filtrate is added 3.68 gof 1-butylamine and the mixture is heated to 60° C. for 6 h. Aftercooling the mixture is partitioned between ethyl acetate and water. Theorganic layer is washed with brine, dried over sodium sulfate andconcentrated to provide 13.28 g of the amidine as a yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 7.55 (m, 2H), 7.4 (m, 3H), 3.37 (bm, 2H), 1.62 (m,2H), 1.42 (m, 2H), 0.95 (t, J=7 Hz, 3H).

1-(1-Butyl)-2-phenylimidazole-5-carboxaldehyde (102). To a solution of101 (13.28 g) and 2-bromo-3-isopropoxyacrolein (22 g) in chloroform (150ml) is added potassium carbonate (15.5 g) and water (19 ml). The mixtureis stirred at room temperature overnight. The aqueous layer is discardedand the organic layer is washed with water (3×100 mL), dried (Na₂SO₄)and concentrated. The residue is purified via flash chromatography (5%MeOH/CHCl₃) to provide the desired imidazole carboxaldehyde as a paleyellow oil (21.55 g). ¹H NMR (400 MHz, CDCl₃) 5 9.75 (s, 1H), 7.90 (s,1H), 7.55 (m, 2H), 7.45 (m, 3H), 4.38 (t, J=8 Hz, 2H), 1.75 (m, 2H),1.22 (m, 2H), 0.91 (t, J=7 Hz, 3H).

Representative preparation of a 1-Alkyl-2-aryl-4-aminomethylimidazole:1-(1-Butyl)-2-phenyl-5-(N,N-di[3,4-methylendioxyphenylmethyl])aminomethylimidazole)

1-(1-Butyl)-2-phenyl-5-hydroxymethylimidazole (103). Aldehyde 102 isdissolved in methanol (150 mL). Sodium borohydride (3 g) is added inportions. After the addition was complete, the reaction is diluted withwater and concentrated. The residue is dissolved in ethyl acetate,washed with brine, dried (Na₂SO₄) and concentrated. The product ispurified by flash chromatography on silica gel (5% MeOH/CHCl₃) to give4.17 g of 103 as a cream colored solid. ¹H-NMR (400 MHz, CDCl₃): δ 0.79(3H, t, d=7.4), 1.18 (2H, m, d=7.4), 1.60 (2H, m, d=7.6), 4.03 (2H, dd,d=7.6), 4.56 (2H, s), 6.84 (1H, s), 7.39–7.50 (3H, m),7.50–7.53 (2H, m).

1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl])aminomethylimidazole(104). Hydroxymethylimidazole 103 (0.82 g) is dissolved in chloroform(10 ml) and treated with thionyl chloride (1 ml). The solution is heatedto 50° C. for 30 min, cooled and evaporated. The residue is washed withbenzene and evaporated to give the intermediate chloromethylhydrochloride as a white powder which is taken up in acetonitrile (30mL). This is added dropwise to a solution of piperonylamine (5 ml) inacetonitrile (10 mL). The reaction is allowed to stand overnight andthen evaporated. The residue is taken up in ethyl acetate and washedwith water. The organic layer is dried (Na₂SO₄) and concentrated.Purification on silica gel (10% MeOH/CHCl₃) provides the product as apale yellow oil (0.91 g). ¹H NMR (400 MHz, CDCl₃): δ 0.79 (3H, t,d=7.4), 1.18 (2H, m, d=7.4), 1.56 (2H, m, d=7.4), 3.75 (4H, s), 4.04(2H, dd, d=8), 5.92 (2H, s), 6.76 (2H, m), 6.84 (1H,s), 6.97 (1H, s),7.38–7.44 (3H, m), 7.53–7.56 (2H, m).

1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-(3,4-methylenedioxyphenylcarboxy]) aminomethylimidazole (105).Compound 104 (160 mg, 0.44 mmol) is dissolved in chloroform (5 ml,pentene stabilized) and treated sequentially with piperonyloyl chloride(100 mg) and triethylamine (1 ml). The mixture is stirred at roomtemperature overnight. The solution is concentrated and the residuetaken up in ethyl acetate. The organic is washed with water, dried(Na₂SO₄) and concentrated. Purification by preparative thin layerchromatography (5% MeOH/CHCl₃) provides compound 105 as a pale yellowoil (240 mg). ¹H-NMR (400 MHz, CDCl₃): δ 0.75 (3H, br), 1.16 (2H, br),1.49 (2H, br), 4.01 (2H, br), 4.54 (2H, br), 4.68 (2H, br), 5.97 (2H,s), 5.99 (2H, s), 6.66 (2H, d, d=7.2), 6.80 (2H, t, d=8), 6.98–7.02 (2H,m), 7.40–7.47 (3H, m), 7.56 (2H, d, d=6.8).

1-(1-Butyl)-2-phenyl-5-(N,N-di[3,4-methylenedioxyphenylmethyl])-aminomethylimidazole (106). Amide 105 (215 mg) intetrahydrofuran (THF, 3 ml) is added dropwise to a solution of alane (1M in THF, 2 ml) and the resulting solution is stirred for 2.5 h at roomtemperature. A solution of sodium hydroxide (15% NaOH, 1 ml) is addedand the mixture is extracted with chloroform. The organic extracts aredried (Na₂SO₄) and concentrated. Purification by preparative thin layerchromatography (10% MeOH/CHCl₃) provided compound 106 as a colorless oil(115 mg). ¹H-NMR (400 MHz, CDCl₃): δ0.70 (3H, t, d=7.6), 0.98 (2H, m,d=7.6), 1.30 (2H, m), 3.44 (4H, s), 3.52 (2H, s), 3.98 (2H, dd, d=8),5.92 (4H, s), 6.74 (4H, s), 6.69 (2H, s), 7.02 (1H, s), 7.36–7.42 (3H,m), 7.54 (2H, dd, d=1.4, 6.6). The hydrochloride salt (m.p. 187–190° C.)was prepared in isopropanol.

Example 2 Preparation of1-(1-butyl)-2-phenyl-5-(1-[N-{3,4-methylenedioxyphenylmethyl}-N-phenylmethyl]amino)ethylimidazole(Compound 108)

1-Butyl-2-phenyl-5-(1-hydroxyethyl)imidazole (107). A solution ofaldehyde 102 (230 mg) in diethyl ether (30 mL) is placed in a separatoryfunnel and treated with a solution of

Preparation of1-(1-Butyl)-2-phenyl-5-(1-[N-[{3,4-methylendioxyphenylmethyl]}-N-[phenylmethyl]aminoethylimidazole)

methyl lithium (1.4 M in THF, 1.5 ml). After 10 min, the solution iswashed with ammonium chloride solution (1 M, 20 ml), dried (Na₂SO₄) andconcentrated. The resulting dark oil is purified by preparative TLC (10%MeOH/CHCl₃) to provide compound 107 as a colorless oil (180 mg). ¹H NMR(400 MHz, CDCl₃) δ7.56 (d, J=2 Hz, 2H), 7.4 (m, 3H), 7.01 (s, 1H), 4.86(q, J=7 Hz, 1H), 4.18 (m, 1H), 4.0 (m, 1H), 1.63 (d, J=6.6 Hz, 3H), 1.63(m, 2H), 1.23 (m, 2H), 0.81 (t, J=7 Hz, 3H).

1-Butyl-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]-N-phenylmethyl)aminoethylimidazole(108). A solution of compound 107 (80 mg) in chloroform (10 ml) istreated with thionyl chloride (1 ml) and heated to 50° C. for 30 min.The solution is then concentrated, diluted with chloroform andreconcentrated to provide the intermediate chloromethyl hydrochloride asan oil. This material is taken up in chloroform (5 ml) and treatedsequentially with N-benzylpiperonylamine (80 mg) and triethylamine.After stirring overnight, the reaction is washed with saturatedpotassium carbonate solution, dried (Na₂SO₄) and concentrated.Purification by preparative thin layer chromatography (10% MeOH/CHCl₃)provides compound 108 as a colorless oil (62 mg). ¹H NMR (400 MHz,CDCl₃) δ 7.46–7.43 (m, 1H), 7.2–7.3 (m, 9H), 6.74–6.86 (m, 4H), 5.94 (s,2H), 4.82 (q, J=6.8 Hz, 1H), 4.33 (m, 2H), 3.78 (s, 2H), 3.53 (s, 2H),1.83 (d, J=6.8 Hz, 3H), 1.62–1.68 (m, 2H), 1.21 (q, J=7.8 Hz, 2H), 0.82(t, J=7.8 Hz, 3H).

Example 3 Preparation of1-Butyl-2-phenyl-4-bromo-5-(N-phenylmethyl-N-[1-butyl])amino-methylimidazole(Compound 110) Preparation of 1(1-Butyl)-2-phenyl-4-bromo-5-[N-phenylmethyl-N-[1-butyl])aminomethylimidazole)

1-Butyl-2-phenyl-5-(N-benzyl-N-butyl)aminomethylimidazole (109). Asolution of compound 102 (115 mg) and N-butylbenzylamine (85 mg) intoluene (10 ml) is allowed to stand overnight. Treatment of the reactionwith sodium borohydride (100 mg) and ethanol (2 mL) followed by aqueousworkup and purification on silica gel (10% MeOH/CHCl₃) provides compound109 as a colorless oil (35 mg). ¹H NMR (400 MHz, CDCl₃) δ7.2–7.5 (m,10H), 6.98 (s, 1H), 4.0 (t, J=8 Hz, 2H), 3.55 (s, 2H), 3.52 (s, 2H),2.42 (t, J=8 Hz, 2H), 1.2–1.55 (m, 6H), 1.05 (m, 2H), 0.84 (t, J=7 Hz,3H), 0.72 (t, J=7 Hz, 3H).

1-Butyl-2-phenyl-4-bromo-5-(N-phenylmethyl-N-[1-butyl])aminomethylimidazole(110). To a solution of 109 (30 mg) in acetonitrile (4 mL) was addedN-bromosuccinimide (16 mg). The resulting mixture was heated to 60° C.and the progress of the reaction followed by TLC. The cooled reactionmixture was diluted with ethyl acetate and washed twice with water.Purification by preparative thin layer chromatography (10% MeOH/CHCl₃)provided compound 110 as a colorless oil (22 mg). ¹H NMR (400 MHz,CDCl₃) δ7.2–7.5 (m, 10H), 3.98 (t, J=8 Hz, 2H), 3.55 (s, 2H), 3.53 (s,2H), 2.46 (t, J=7 Hz, 2H), 1.52 (m, 2H), 1.3 (m, 4H), 0.98 (q, J=7 Hz,2H), 0.84 (t, J=7 Hz, 3H), 0.70 (t, J=7 Hz, 3H).

Example 4 Preparation of1-(1-Butyl)-2-phenyl-4-methyl-5-(N-[3,4-methylenedioxyphenyl-methyl]-N-phenylmethyl)aminomethylimidazole.(Compound 114)

1-Butyl-2-phenyl-4-methylimidazole (112). To a solution of4-methyl-2-phenylimidazole (111, 15.8 g) in dimethylformamide (100 ml)is added sodium hydride (4.4 g, 60% in mineral oil) in small portions.After the addition is complete, the mixture was stirred for anadditional 20 min and treated with 1-iodobutane (18.8 g). The reactionis fitted with a reflux condensor and heated at 100° C. for 12 h. Thecooled reaction mixture is partitioned between water (300 ml) anddiethyl ether (300 ml). The organic layer is washed with water (3×200ml), dried (Na₂SO₄) and concentrated to provide 20.5 g ofN-butylimidazoles. Analysis by ¹H-NMR and GC-MS revealed mixture of1-butyl-2-phenyl-4-methylimidazole (112) and1-butyl-2-phenyl-5-methylimidazole in a ratio of 11.5/1. The mixture wascarried on to the next step without purification.

1-Butyl-2-phenyl-4-methyl-5-hydroxymethylimidazole (113). A solution of112 (1 g) in acetic acid (10 mL) and 40% aqueous formaldehyde (2 mL) isrefluxed for 14 h. The reaction is then concentrated and dried byrepeated reconcentration with toluene. The residue is purified by columnchromatography (10% MeOH/CHCl₃). The fractions are assayed by GC andthose fractions uncontaminated by the isomeric hydroxymethylimidazolecombined. Concentration of the combined fractions provides compound 113(320 mg) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.4–7.6 (m,6H), 4.61 (s, 2H, CH₂OH), 4.02 (t, J=7 Hz, 2H, NCH₂), 2.22 (s, 3H, Me),1.63 (m, 2H, 1.25 (m, 2H), 0.81 (t, J=7 Hz, 3H).

Preparation of1-(1-Butyl)-2-phenyl-4-methyl-5-(N-[3,4methylenedioxyphenyl]-N-phenylmethyl)aminomethylimidazole

1-Butyl-2-phenyl-4-methyl-5-(N-benzyl-N-butyl)aminomethylimidazole(114). Compound 114 (23 mg) is prepared from 113 (50 mg) in a methodsimilar to that used to obtain compound 108. ¹H NMR (400 MHz, CDCl₃)δ7.5–7.55 (m,2H), 7.38–7.42 (m, 3H), 7.23–7.30 (m, 5H), 3.95 (t, J=7.5Hz, 2H), 3.55 (s, 2H), 3.53 (s, 2H), 2.40 (t, J=7 Hz, 2H), 2.22 (s, 3H),1.25–1.40 (m, 6H), 1.05 (m, 2H), 0.82 (t, J=7 Hz, 3H). 0.70 (t, J=7 Hz,3H); MS (LCMS) m/e 390 (M⁺+1)

Example 5 Preparation of a cycloalkylimidazole compound:4-{[butyl(1-butyl-2-phenyl(4,5,6-trihydrocyclopenta[3,2-d]imidazol-6-yl)amino]methyl}-3-chlorophenol

N-(n-butyl)-benzamidine (120). To a solution of methyl benzimidatehydrochloride (12 g, 0.07 mole) in dimethylformamide (DMF, 20 mL) isadded 7 ml of triethylamine at 0° C. After 2 h the reaction is filteredto remove triethylamine hydrochloride. To the filtrate is added 3.68 gof 1-butylamine and the mixture is heated to 60° C. for 6 h. Aftercooling the mixture is partitioned between ethyl acetate and water. Theorganic layer is washed with brine, dried over sodium sulfate andconcentrated to provide 13.28 g of the amidine as a yellow oil. ¹H NMR(CDCl₃) 7.55 (m, 2H), 7.4 (m, 3H), 3.37 (bm, 2H), 1.62 (m, 2H), 1.42 (m,2H), 0.95 (t, J=7 Hz, 3H).

2-Bromo-3-methoxycyclopentenone (131) is prepared via the method ofCurran et al JACS, vol 112, page 5601. To a suspension of1,3-cyclopentanedione (10 g) in chloroform (700 ml) is added aN-bromosuccinimide (18.2 g). The mixture is refluxed for 2 h, cooled andconcentrated. Methanol (700 mL) and p-toluenesulfonic acid (1 g) areadded and the solution is refluxed overnight. The mixture isconcentrated to 100 ml, diluted with methylene chloride (500 mL) andpoured into water. The aqueous layer is discarded and the organic layeris washed with water (3×100 mL), dried (Na₂SO₄) and concentrated. Theresidue is crystallized from ethyl acetate to give 131 as tan crystals(1.67 g).

1-Butyl-2-phenyl-4,5-dihydrocyclopenty[1,2-d]imidazol-6-one (Compound132). To a mixture of amidine 130 (3.52 g, 20 mmol) and enone 13 (4.58g, 24 mmol) in chloroform (40 mL) and water (5 mL) was added solidpotassium carbonate (3.32 g, 24 mmol). The resulting mixture is refluxedovernight. After cooling, the mixture is washed with water, dried(Na₂SO₄) and concentrated. Purification on silica gel eluting with 25%ethyl acetate/hexane gives the desired product 132 (3.0 g) LC-MS (M⁺+1):255. ¹H-NMR (δ, CDCl₃): 0.84 (t, J=7.6 Hz, 3H), 1.23 (dt, J=7.0, 7.6 Hz,2H), 1.81 (m, 2H), 2.95 (m, 4H), 4.13 (t, J=7.6 Hz, 2H) 7.5–7.45 (m,3H), 7.76–7.6 (m, 2H) ppm.1-Butyl-2-phenyl-4,5-dihydrocyclopenty[1,2-d]imidazol-6-ol (Compound133). To a solution of 132 (2.68 g) in methanol (20 mL) is added sodiumborohydride (1.5 equiv) and the mixture stirred overnight. The mixtureis concentrated, diluted with chloroform and washed with 0.5 N NH₄Clsolution. The organic layer is dried (Na₂SO₄) and concentrated toprovide the desired product 133. LC-MS (M+1) 257.Butyl(1-butyl-2-phenyl-4,5,6-trihydrocyclopentyl[3,2-d]imidazol-6-yl))amine(Compound 135). Compound 133 (2 g) is dissolved in chloroform (20 mL)and thionyl chloride (5 mL) and the resulting solution is stirred atroom temperature overnight. The solvent and excess thionyl chloride areevaporated and the crude chloride 134 was dissolved in n-butylamine (10mL). After 2 h, the excess butylamine was evaporated, the residuedissolved in ethyl acetate and the organic solution washed with 5% NaOHsolution and water. The organic layer was dried and concentrated. Theorganic residue is purified by column chromatography on silaica geleluting with 10% CH₃OH in CHCl₃ to provide the desired secondary amine135 in 82% yield. LC-MS (M+1) 312 ¹H-NMR (chemical shift, CDCl₃): 0.83(t, J=7.2 Hz, 3H), 0.9 (t, J=7.2 Hz, 3H), 1.23 (q, J=7.2 Hz, 2H), 1.35(q, J=7.2 Hz, 2H), 1.46 (m, 2H), 1.70 (m, 2H), 2.24 (m, 1H), 2.55–2.66(m, 4H), 2.73–2.80 (m, 2H), 3.97–4.04 (m, 2H), 4.30 (d, J=5.6 Hz, 1H),7.37–7.44 (m, 3H), 7.55–7.57 (m, 2H).4-{[Butyl(1-butyl-2-phenyl(4,5,6-trihydrocyclopenta[3,2-d]imidazol-6-yl))amino]methyl}-3-chlorophenol(Compound 5, Table 1). To a solution of compound 135 (50 mg) in1,2-dichloroethane (2 mL) and 2-chloro-4-hydroxybenzaldehyde (30 mg) isadded sodium triacetoxyborohydride (100 mg). The resulting mixture isallowed to stir overnight. After washing with 0.5 ammonium chloridesolution, the organic layer is dried (Na₂SO₄) and concentrated.Purification using preparative thin layer chromatography eluting with 5%CH₃OH/CHCl₃ provides the desired product 136 as an oil (21 mg). LC-MS(M+1) 452, (M−1) 450. ¹H-NMR (chemical shift, CDCl₃): 0.74 (t, J=7.2 Hz,3H), 0.83 (t, J=7.2 Hz, 3H), 1.11 (q, J=7.2 Hz, 2H), 1.21–1.33 (m, 2H),1.41–1.51 (m, 4H), 2.34–2.44 (m, 3H), 2.51–2.57 (m, 1H), 2.60–2.67 (m,1H), 2.69–2.75 (m, 1H), 3.38 (d, J=7.6 Hz, 1H), 3.47 (d, J=13.6 Hz, 1H),3.65 (d, J=13.6 Hz, 1H), 3.78–3.96 (m, 1H), 6.62 (dd, J=8,2 Hz, 1H),6.78 (d, J=2 Hz, 1H), 7.07 (d, J=8 Hz, 1H), 7.35–7.41 (m, 3H), 7.45–7.48(m, 2H).

Preparation of 4-{[Butyl(1-butyl-2-phenyl(4,5,6-trihydrocyclopenta[3,2-d]imidazol-6-yl))amino]methyl}-3-chlorophenol

Example 6 Preparation of2-phenyl-4-(N,N-di{2H-Benzo[3,4-d]-1,3-dioxolan-5-ylmethyl}amino)methyl-3-butylpyridine

4-Phenyl-5-butyloxazole (140). A mixture of α-bromohexanophenone (25.5g, 0.1 mole), ammonium formate (22 g, 0.35 mole) and formic acid (110mL) was refluxed with stirring for 3 h. The reaction mixture was pouredonto ice and made basic with 10 N NaOH and extracted with ether. Theorganic layer was washed with water, dried over sodium sulfate andconcentrated. The crude product was purified by flash chromatography onsilica gel eluting with 20% ethyl acetate in hexane. To provide thedesired compound as an oil (8.3 g, 41%); ¹H NMR (δ, CDCl₃, 400 MHz) 7.55(m, 2H), 7.40 (s, 1H), 7.34 (dd, J=7,7 Hz, 2H), 7.22 (dd, J=7, 7 Hz,1H), 2.74 (m, 2H), 1.6 (m, 2H), 1.30 (m, 2H), 0.84 (t, J=7 Hz, 3H) ppm.

2-Phenyl-3-butylisonicotinic acid (141). A mixture of4-phenyl-5-butyloxazole (12, 5 g, 25 mmol) and maleic acid (3.5 g, 30mmol) is heated at 100° C. for 30 min. After cooling, the semisolid massis triturated with ether and the solid collected by filtration. ¹H NMR(δ, CDCl₃, 400 MHz) 11.68 (brs, 1H), 8.72 (d, J=6.0 Hz, 1H), 7.73 (d,J=5.6 Hz, 1H), 7.48–7.51 (m, 2H), 7.42–7.44 (m, 2H), 6.25 (s, 1H), 2.86(d, J=7.6 Hz, 2H), 1.36 (m, 2H), 1.11 (dt, J=7.6, 7.2 Hz, 2H), 0.68 (t,J=7.6 Hz, 3H). MS (M+1): 256, (M−1) 254.

2-Phenyl-4-hydroxymethyl-3-butylpyridine (142). 4 mL of a 1M solution oflithium aluminum hydride in tetrahydrofuran is added to a solution of2-phenyl-3-butylisonicotinic acid (13, 510 mg, 2 mmol) intetrahydrofuran (20 mL). The reaction is stirred overnight and thenquenched with 5 mL of 15% aqueous NaOH. The resulting mixture isextracted with ether, dried (Na₂SO₄) and concentrated to provide thedesired hydroxymethylpyridine as an oil (470 mg). LC-MS (M+1): 242; ¹HNMR ( , CDCL₃) 8.35 (1H, d, J=5.2 Hz), 7.30–7.39 (6H, m), 4.59 (2H, s),2.43 (2H, t, J=8.0 Hz), 1.23 (2H, m), 1.13 (2H, m), 0.70 (3H, t, J=7.2Hz).

2-Phenyl-4-({2H-benzo[3,4-d]-1,3-dioxolan-5-ylmethyl})aminomethyl-3-butylpyridine(143). Thionyl chloride (200 mg, 1.67 mmol) is added to a solution of2-phenyl-4-hydroxymethyl-3-butylpyridine (400 mg, 1.66 mmol) in pentenestabilized chloroform (8 mL) and the mixture is heated to 50° C. for 2h. The resulting mixture is cooled, washed with saturated sodiumbicarbonate solution, dried (Na₂SO₄) and concentrated. The resultingcrude chloride is taken up in dimethylformamide (10 mL) and addeddropwise to a refluxing solution of piperonylamine (1.0 g, 4 equiv) indimethylformamide (30 mL) containing 3 g of powdered potassiumcarbonate. After the addition is complete, the resulting mixture isrefluxed for an additional 3 h, cooled and partitioned between water(200 mL) and ether (100 mL). The ethereal layer is washed 2 times withwater, dried (Na₂SO₄) and concentrated. The resulting material ispurified by chromatography on silica eluting with 10% CH₃OH/CHCl₃ togive the desired secondary amine 15. LC-MS (M+1): 375.3; ¹H-NMR (δ,CDCl₃): 0.73 (3H, t, J=7.2 Hz), 1.15 (2H, m J=7.2 Hz), 1.30 (2H, m),2.58 (2H, t, J=8.0 Hz), 3.79 (2H, s), 3.83 (2H, s), 5.93 (2H, s),6.75–6.82 (2H, m), 6.89 (1H, d, J=1.2 Hz), 7.36–7.42 (6H, m), 8.45 (1H,d, J=4.8 Hz) ppm.

2-Phenyl-4-(N,N-di{2H-benzo[3,4d]1,3-dioxolan-5-ylmethyl})aminomethyl-3-butylpyridine(144). To a solution of 14 (38 mg) in dichloroethane (5 mL) was addedpiperonal (30 mg). The resulting mixture was stirred for 3 h after whichtime sodium triacetoxyborohydride (150 mg) is added in one portion andthe resulting mixture is stirred overnight. The reaction mixture wasquenched with 10% ammonium hydroxide solution (5 ml). The organic layeris washed with water and extracted with 1N HCl solution. The acidicextract is made basic with 1N NaOH solution and extracted withchloroform. The organic extract is dried (Na₂SO₄) and concentrated. Theresulting oil is purified on preparative thin layer chromatographyeluting with 10% CH₃OH/CHCl₃ to give the desired tertiary amine 144 asan oil (18 mg). LC-MS (M+1): 509.4; ¹H-NMR (5, CDCl₃): 0.71 (3H, t,J=7.2 Hz), 1.10 (2H, m, J=7.2 Hz), 2.60 (2H, t, J=8.0 Hz), 3.48 (4H, s),3.58 (2H, s), 5.94 (4H, s), 6.75 (1H, d, J=8.0 Hz),6.80 (1H, dd, J=0.8,8.0 Hz), 6.91 (1H, d, J=0.8 Hz), 7.36–7.43 (5H, m), 7.56 (1H, d, J=5.2Hz), 8.47 (1H, d, J=5.2 Hz) ppm.

Preparation of 2-Phenyl(N,N-di{2H-benzo[3,4d]-1,3-dioxolan-5-ylmethyl})aminomethyl-3-butylpyridine

Example 7 Preparation of an Arylpyrazole1,3-diphenyl-4-(N-{2H-benzo[3,4-d]-1,3-dioxolan-5-ylmethyl}-N-butylamino)methyl-5-propylpyrazole

N′-Phenyl-N-phenylhydrazone (150). Benzaldehyde (9.81 g, 9.25 mmol) isadded at 0–5° C. to a solution of phenyl hydrazine (10 g, 9.25 mmol) inethanol (100 mL). A cream colored solid forms and the reaction mixtureis allowed to stand for 2h. The solid is collected by filtration, washedwith ice-cold ethanol and dried under vacuum to provide the desiredcompound, compound 150 (14.92 g);LC-MS m/z 197.2, ¹H NMR (δ, CDCl₃, 400MHz) ppm.

Ethyl 1,3-diphenyl-5-propylpyrazole-4-carboxylate (152). A mixture of150 (5 g, 25.5 mmol) and ethyl butyrylacetate (20.2 g, 128 mmol) and acatalytic amount of zinc chloride is heated at 125° C. under an airatmosphere for 3h. The reaction vessel is fitted with a short pathdistillation head and excess ethyl butyrylacetate iss distilled awayunder vacuum. The resulting material is purified by columnchromatography on silica eluting with 10% ethyl acetate in hexanes toprovide the desired ester 152 as a yellow oil (6.39 g) whichcrystallizes upon standing. Recrystallization from diisopropyl etherprovides a white solid. ¹H NMR (δ, CDCl₃, 400 MHz) MS (M+1): 335.2

1,3-Diphenyl-4-hydroxymethyl-5-propylpyrazole (153). To a solution ofester 153 (670 mg, 2 mmol) in tetrahydrofuran (20 mL) is added 4 mL of a1M solution of lithium aluminum hydride in tetrahydrofuran. The reactionis stirred overnight and then quenched with 5 mL of 15% aqueous NaOH.The resulting mixture is extracted with ether, dried (Na₂SO₄) andconcentrated to provide the desired hydroxymethylpyrazole as an oil (505mg). LC-MS (M+1): 293.3; ¹H NMR (δ, CDCL₃) 7.86 (dd, J=8.4 Hz, 2H),7.34–7.52 (m, 8H), 4.65 (s, 2H), 2.72 (t, J=8.0 Hz, 2H), 1.52 (m, 2H),0.87 (t, J=7.6 Hz, 3H).

[(1,3-Diphenyl-5-propylpyrazol-4 μl)methyl]butylamine (154). To asolution of 18 (289 mg) in pentene stabilized chloroform (8 mL) is addedthionyl chloride (1 mL) and the mixture heated to 60° C. for 2 h. Theresulting mixture is cooled, washed with saturated sodium bicarbonatesolution, dried (Na₂SO₄) and concentrated. The resulting crude chlorideis taken up in dimethylformamide (3 mL) and added dropwise to a solutionof butylamine (1.0 g) in dimethylformamide (10 mL) containing 2 g ofpowdered potassium carbonate. After the addition is complete, theresulting mixture is stirred for an additional 3 h and partitionedbetween water (20 mL) and ether (10 mL). The ethereal layer is washed 2times with water, dried (Na₂SO₄) and concentrated. The resultingmaterial is purified by chromatography on silica eluting with 10%CH₃OH/CHCl₃ to give the desired secondary amine 155 (190 mg). LC-MS(M+1): 348.3; ¹H-NMR (δ, CDCl₃): 7.87 (dd, J=8.0, 1.6 Hz, 2H), 7.32–7.48(m, 8H), 3.77 (s, 2H), 2.70 (m, 4H), 1.48 (m, 4H), 1.34 (m, 2H), 0.91(t, J=7.6 Hz, 3H), 0.87 (t, J=7.6 Hz, 3H) ppm.

1,3-Diphenyl-4-(N-{2H-benzo[3,4-d]-1,3-dioxolan-5-ylmethyl}-N-butylamino)methyl-5-propylpyrazole(Compound 155). To a solution of 154 (35 mg) in dichloroethane (5 mL) isadded piperonal (30 mg). The resulting mixture is stirred for 3 h afterwhich time sodium triacetoxyborohydride (150 mg) is added in one portionand the resulting mixture is stirred overnight. The reaction mixture isquenched with 10% ammonium hydroxide solution (5 ml). The organic layeris washed with water and extracted with 1N HCl solution. The acidicextract is made basic with 1N NaOH solution and extracted withchloroform. The organic extract is dried (Na₂SO₄) and concentrated. Theresulting oil is purified on preparative thin layer chromatographyeluting with 10% CH₃OH/CHCl₃ to give the desired tertiary amine(Compound 155) as an oil (24 mg). LC-MS (M+1): 482.5; ¹H-NMR (δ, CDCl₃):7.87 (d, J=7.2 Hz, 2H), 7.47 (d, J=4.4 Hz, 4H), 7.33–7.43 (m, 4H), 6.77(s, 1H), 6.70 (s, 2H), 5.92 (s, 2H), 3.56 (s, 2H), 3.42 (s, 2H), 2.74(t, J=8.0 Hz, 2H), 2.37 (t, J=7.2 Hz, 2H), 1.42 (m, 4H), 1.21 (m, 2H),0.83 (t, J=7.6 Hz, 3H), 0.81 (t, J=7.2 Hz, 3H) ppm.

Preparation of1,3-Diphenyl-4-(N-{2H-benzo[3,4-d]-1,3-dioxolan-5-ylmethyl}-N-butylamino)methyl-5-propylpyrazole

Example 8 Synthesis ofN-(1-fluorobenzyl)-N-indan-2-yl-2-(6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)acetamide (162)

A mixture of 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolinehydrochloride (160, 153 mg, 0.5 mmol),N-(1-fluorobenzyl)-N-indan-2-yl-2-bromoacetamide (161, 180 mg, 0.5 mmol)and potassium carbonate (500 mg) in acetonitrile is heated at 80° C.overnight. After cooling, the mixture is filtered and concentrated. Theresulting residue is purified by column chromatography eluting with 5%methanol in chloroform to provide the title product (162) as a thick oil(215 mg, 78%). ¹H NMR (CDCl₃) 6.8–7.3 (m, 14H), 6.60(s, 1H), 6.05 (s,1H),

Example 9 Preparation of 4-Trifluoromethyl-biphenyl-2-carboxylic acidbenzo[1,3]dioxol-5-ylmethyl-benzyl-amide (174)

1,1′-carbonyldiimidazole (175 mg) is added to a solution of2-iodobenzoic acid (248 mg, 1 mmol)(170) in tetrahydrofuran (THF, 5 ml).The resulting mixture is stirred overnight at room temperature. Asolution of N-3,4-methylenedioxybenzyl-N-benzylamine (241 mg, 1equiv)(171) in THF (2 mL) is added and the resulting solution is stirredfor 1 h, quenched with water and extracted with diethyl ether. Theorganic extracts are dried (Na₂SO₄) and concentrated. The residualmaterial is taken up in dimethoxyethane (10 mL) and a catalytic amount(20 mg) of tetrakis(triphenylphosphine)palladium(0) is added. Theresulting mixture is stirred under an argon atmosphere for 10 min andsolid 4-trifluoromethyllphenylboronic acid (150 mg) is added in oneportion. A second phase of 1N aqueous Na₂SO₄ is added and the mixture iswarmed to 80° C. for 6 h under a argon atmosphere. The solution iscooled, diluted with water and ethyl acetate and filtered through a padof celite. The organic phase is dried over sodium sulfate andconcentrated. Purification on silica eluting with 20% ethyl acetate inhexane provided the desired biphenylamide product (174)(410 mg). Theproton NMR displays a doubled pattern commonly observed for amides whichpossess some rotational restriction about the amide nitrogen at roomtemperature. The ratio of the rotomers is approximately equal. ¹H NMR(CDCl₃) 3.50 and 3.62 (two doublets, J=X Hz, 1H), 3.72 and 3.83 (twodoublets, J=X Hz, 1H), 4.10 and 4.18 (two doublets, J=X Hz, 1H), 5.09and 5.16 (two doublets, J=x Hz, 1H), 5.95 (d, J=X Hz, 2H, OCH₂O), 6.30(m, 1.5H), 6.46 (d, J=1 Hz, 0.5 Hz), 6.60 and 6.66 (two doublets, J=XHz, 1H), 6.80 (bd, J=X Hz, 1H), 6.86 (m, 1H), 7.16–7.62 (m, 11H).

4′-Trifluoromethyl-biphenyl-2-carboxylic acidbenzo[1,3]dioxol-5-ylmethyl-benzyl-amide Example 10 Preparation ofN-Benzol[1,3]dioxol-5-ylmethyl-N-benzyl-2-pyrazol-1-yl-benzamide

2-Pyrazol-1-yl-benzonitrile, Compound 177. A solution of 20 mmol of2-fluorobezonitrile and 40 mmol of pyrrazole is mixed together indimethylformaide with 1 equivalent of potassium hydroxide and acatalytic amount of 18-crown-6. The mixture is stirred at roomtemperature overnight, quenched with water and ethyl acetate andextracted with ethyl acetate. The organic extract is washed repeatedlywith 1 N NaOH solution. The organic layer is then diluted with ether andwashed with 1N HCl solution, dried and concentrated. ¹H NMR (CDCl₃) 6.55(t, J=2 Hz, 1H), 7.42 (M, 1H), 7.65–7.82 m, 4H), 8.15 (d, J=1 Hz, 1H).2-Pyrazol-1-yl-benzoic acid. Compound 178. A solution of compound 177 inconc HCl is refluxed overnight, cooled and concentrated. The product isprecipitated by addition of 1 N NaOH until pH of 5–6, filtered anddried. 1H (CDCl₃) 6.52 (t, J=3 Hz, 1H), 7.40 (d, J=8 Hz, 1H), 7.50 (t,J=8 Hz, 1H) 7.62 (t, J=8 hz, 1H), 7.81 (m, 2H), 8.12 (d, J=8 Hz, 1H).N-Benzo[1,3]dioxol-5-ylmethyl-N-benzyl-2-pyrazol-1-yl-benzamide,Compound 179. 1.1 equiv of carbonyl diimidazole is added to a solutionof benzoic acid 178 (200 mg) in tetrahydrofuran (5 mL); the reaction isstirred at room temperature for 3 h. After this timeN-piperonyl-N-benzylamine (0.25 g) is added in one portion. After 30min, the reaction is filtered, diluted with ether and washed with water.The organic layer is dried (Na₂SO₄) and purified over columnchromatography to provide the desired product (390 mg). The proton NMRdisplays a typically doubled pattern. ¹H (CDCl₃) 3.83 and 4.32 (twodoublets, J=16 Hz, 1H), 3.91 (two doublets, J=8 Hz, 1H), 4.18 twodoublets (J=6 Hz, 1H), 5.0 and 5.1 (two doublets, J=14 Hz, 1H), 5.93 and5.98 (s and doublet, J=2 Hz, 2H, OCH₂O), 6.35–6.40 (m, 2H), 6.51 (d, J=4Hz, 0.5H), 6.4 (m, 1.5H), 7.0–7.88 m, 15H). LC-MS 412.3

Example 11 Preparation ofN-benzoyl-N-(4-methoxybenzyl)-N-(1-propyl-2-methyleno-7-azabenzimidazole2-aminopropyl-3-nitropyridine

2-chloro-3-nitroaminopyridine (180) (5.5 g, 35 mmol) is dissolved in 150mL acetonitrile at room temperature. Propylamine (21 g, 350 mmol) isadded dropwise and the reaction mixture is stirred for 5 hours at roomtemperature. The solvent and excess propylamine are removed in vacuo.The residue is dissolved in 150 mL ethyl acetate and washed once with100 mL saturated NaHCO₃ solution and once with 100 mL brine. The organiclayer is dried over MgSO4, filtered, and the solvent removed in vacuo toafford 6.3 g of 2-aminopropyl-3-nitropyridine (181).

2-aminopropyl-3-aminopyridine

2-aminopropyl-3-nitropyridine (171)(6.3 g, 35 mmol) is dissolved in 100mL 1/1 ethyl acetate/ethanol in a Parr shaker bottle. Nitrogen isbubbled through the solution for 2 minutes followed by the addition of10% Pd/C (500 mg). The suspension is hydrogenated on a Parr apparatusunder 40 psi of H₂ until hydrogen uptake ceased. The suspension isfiltered through Celite and the solvent evaporated in vacuo to afford5.3 g of the 2-aminopropyl-3-aminopyridine (182).

1-propyl-2-chloromethyl-7-azabenzimidazole

2-aminopropyl-3-aminopyridine (172) (5.3 g, 35 mmol) is dissolved in 100mL CHCl₃ at room temperature. Ethyl chloromethylimidate hydrochloride(14 g, 89 mmol) is added followed by K₂CO₃ (25 g, 180 mmol). Thesuspension was stirred vigorously at room temperature for 3 hours. Thereaction mixture is filtered through Celite and the solvent removed invacuo. The residue is passed through a short plug of silica gel elutingwith ethyl acetate to afford 3.7 g of1-propyl-2-chloromethyl-7-azabenzimidazole (183).

1-propyl-2-(4-methoxybenzylamino)methyl-7-azabenzimidazole

4-Methoxybenzylamine (3.8 g, 27 mmol) is dissolved in 20 mL dryacetonitrile. 1-propyl-2-chloromethyl-7-azabenzimidazole (173)(940 mg,4.5 mmol) dissolved in 4.5 mL acetonitrile is added dropwise. Themixture is stirred 10 hours at room temperature. The solvent is removedin vacuo and the residue dissolved in 20 mL ethyl acetate. This solutionis washed once with 20 mL 1 N NaOH, once with 20 mL water, once with 20mL 5% HOAc in water, then once with 5 N NaOH. The organic phase wasdried over MgSO₄, filtered, then concentrated in vacuo. The productmixture is purified by flash chromatography eluting with ethyl acetatefollowed by 95/5/1 ethyl acetate/methanol/triethylamine to afford 850 mgof the 1-propyl-2-(4-methoxybenzylamino)methyl-7-azabenzimidazole (184).

N-benzoyl-N-(4-methoxybenzyl)-N-(1-propyl-2-methyleno-7-azabenzimidazole

1-propyl-2-(4-methoxybenzylamino)methyl-7-azabenzimidazole (174)(19 mg,0.06 mmol) is dissolved in 0.6 mL toluene. Saturated sodium bicarbonatesolution in water (0.3 mL) is added followed by benzoyl chloride (11 mg,0.08 mmol). The reaction mixture is stirred at room temperature for 10hours. It is then diluted with 5 mL ethyl acetate and transferred to aseparatory funnel. The aqueous layer is removed and the organic phasewashed once with 1N NaOH, once with 5 mL water, then and once with mLbrine. The organic phase is dried over MgSO₄, filtered and the solventremoved in vacuo. The product is purified by preparatory tlc elutingwith 1/1 ethyl acetate/hexanes to afford 20 mg of the desired compound(185). NMR 400 MHz (CDCl₃) 8.39 ppm (br d, 1H), 8.15 ppm (br d, 1H),7.52 ppm (m, 1.5H), 7.40 ppm (s, 1.5H), 7.22 (m, 1H), 7.18 ppm (br d,1H), 6.83 ppm, (d, J=4 Hz, 2H), 4.93 ppm (br s, 2H), 4.71 ppm (br s,1H), 4.39 ppm (br s, 1H), 3.79 ppm (s, 3H), 1.89 ppm (br m, 2H), 0.98pp, (br t, 3H).

Example 12

Assay for C5a Receptor Mediated Chemotaxis

This assay is a standard assay of C5a receptor mediated chemotaxis.

Human promonocytic U937 cells or purified human or non-humanneutrophilis are treated with dibutyryl cAMP for 48 hours prior toperforming the assay. Human neutrophils or those from another mammalianspecies are used directly after isolation. The cells are pelleted andresuspended in culture media containing 0.1% fetal bovine serum (FBS)and 10 ug/ml calcein AM (a fluorescent dye). This suspension is thenincubated at 37° C. for 30 minutes such that the cells take up thefluorescent dye. The suspension is then centrifuged briefly to pelletthe cells, which are then resuspended in culture media containing 0.1%FBS at a concentration of approximately 3×10⁶ cells/mL. Aliquots of thiscell suspension are transferred to clean test tubes, which containvehicle (1% DMSO) or varying concentrations of a compound of interest,and incubated at room temperature for at least 30 minutes. Thechemotaxis assay is performed in ChemoTx™ 101–8, 96 well plates (NeuroProbe, Inc. Gaitherburg, Md.). The bottom wells of the plate are filledwith medium containing 0–10 nM of C5a, preferably derived from the samespecies of mammal as are the neutrophils or other cells (e.g., human C5afor the human U937 cells). The top wells of the plate are filled withcell suspensions (compound or vehicle-treated). The plate is then placedin a tissue culture incubator for 60 minutes. The top surface of theplate is washed with PBS to remove excess cell suspension. The number ofcells that have migrated into the bottom well is then determined using afluorescence reader. Chemotaxis index (the ratio of migrated cells tototal number of cells loaded) is then calculated for each compoundconcentration to determine an IC₅₀ value.

As a control to ensure that cells retain chemotactic ability in thepresence of the compound of interest, the bottom wells of the plate maybe filled with varying concentrations chemo-attractants that do notmediate chemotaxis via the C5a receptor, e.g. zymosan-activated serum(ZAS), N-formylmethionyl-leucyl-phenylalanine (FMLP) or leukotriene B4(LTB4), rather than C5a, under which conditions the compounds of theinvention preferably do not inhibit chemotaxis.

Preferred compounds of the invention exhibit IC₅₀ values of less than 1μM in the above assay for C5a mediated chemotaxis.

Example 13

Determination of dopamine D₄ receptor binding activity

The following assay is a standard assay for determining the bindingaffinity of compounds to dopamine D₄ receptors.

Pellets of Chinese hamster ovary (CHO) cells containing recombinantlyexpressing primate dopamine D₄ receptors are used for the assays. Thedopamine D₄ receptor expression vector may be the pCD-PS vectordescribed by Van Tol et al. (Nature (1991) 358: 149–152). The sample ishomogenized in 100 volumes (w/vol) of 0.05 M Tris HCl buffer containing120 mM NaCl, 5 mM MgCl₂ and 1 mM EDTA at 4° C. and pH 7.4. The sample isthen centrifuged at 30,000×g and resuspended and rehomogenized. Thesample is then centrifuged as described and the final tissue sample isfrozen until use. The tissue is resuspended 1:20 (wt/vol) in 0.05 M TrisHC₁ buffer containing 120 mM NaCl.

Incubations for dopaminergic binding are carried out at 25° C. andcontain 0.4 ml of tissue sample, 0.1 nM ³H-YM 09151-2 (Nemonapride,cis-5-Chloro-2-methoxy-4-(methylamino)-N-(2-methyl-2-(phenylmethyl)-3-pyrrolidinyl)benzamide)and the compound of interest in a total incubation of 1.0 ml.Nonspecific binding is defined as that binding found in the presence of1 uM spiperone; without further additions, nonspecific binding is lessthan 20% of total binding.

Example 14 Preparation of radiolabeled probe compounds of the invention

The compounds of the invention are prepared as radiolabeled probes bycarrying out their synthesis using precursors comprising at least oneatom that is a radioisotope. The radioisotope is preferably selectedfrom of at least one of carbon (preferably ¹⁴C), hydrogen (preferably³H), sulfur (preferably ³⁵S), or iodine (preferably 125I). Suchradiolabeled probes are conveniently synthesized by a radioisotopesupplier specializing in custom synthesis of radiolabeled probecompounds. Such suppliers include Amersham Corporation, ArlingtonHeights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRIInternational, Menlo Park, Calif.; Wizard Laboratories, West Sacramento,Calif.; ChemSyn Laboratories, Lexena, Kans.; American RadiolabeledChemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea,Calif. Tritium labeled probe compounds are also conveniently preparedcatalytically via platinum-catalyzed exchange in tritiated acetic acid,acid-catalyzed exchange in tritiated trifluoroacetic acid, orheterogeneous-catalyzed exchange with tritium gas. Such preparations arealso conveniently carried out as a custom radiolabeling by any of thesuppliers listed in the preceding paragraph using the compound of theinvention as substrate. In addition, certain precursors may be subjectedto tritium-halogen exchange with tritium gas, tritium gas reduction ofunsaturated bonds, or reduction using sodium borotritide, asappropriate.

Example 15 Baculoviral Preparations (For C5a Expression)

The human C5a (hC5a) receptor baculoviral expression vector wasco-transfected along with BACULOGOLD DNA (BD PharMingen, San Diego,Calif.) into Sf9 cells. The Sf9 cell culture supernatant was harvestedthree days post-transfection. The recombinant virus-containingsupernatant was serially diluted in Hink's TNM-FH insect medium (JRHBiosciences, Kansas City) supplemented Grace's salts and with 4.1 mML-Gln, 3.3 g/L LAH, 3.3 g/L ultrafiltered yeastolate and 10%heat-inactivated fetal bovine serum (hereinafter “insect medium”) andplaque assayed for recombinant plaques. After four days, recombinantplaques were selected and harvested into 1 ml of insect medium foramplification. Each 1 ml volume of recombinant baculovirus (at passage0) was used to infect a separate T25 flask containing 2×10⁶ Sf9 cells in5 mls of insect medium. After five days of incubation at 27° C.,supernatant medium was harvested from each of the T25 infections for useas passage 1 inoculum. Two of seven recombinant baculoviral clones werethen chosen for a second round of amplification, using 1 ml of passage 1stock to infect 1×10⁸ cells in 100 ml of insect medium divided into 2T175 flasks. Forty-eight hours post infection, passage 2 medium fromeach 100 ml prep was harvested and plaque assayed for titer. The cellpellets from the second round of amplification were assayed by affinitybinding as described below to verify recombinant receptor expression. Athird round of amplification was then initiated using a multiplicity ofinfection of 0.1 to infect a liter of Sf9 cells. Forty hourspost-infection the supernatant medium was harvested to yield passage 3baculoviral stock.

The remaining cell pellet is assayed for affinity binding using the“Binding Assays” described by DeMartino et al., 1994, J. Biol. Chem. 269#20, pp. 14446–14450 at page 14447, adapted as follows. Radioligand is0.005–0.500 nM [¹²⁵I]C5a (human recombinant), New England Nuclear Corp.,Boston, Mass.; the hC5a receptor-expressing baculoviral cells are usedinstead of 293 cells; the assay buffer contains 50 mM Hepes pH. 7.6, 1mM CaCl₂, 5 mM MgCl₂, 0.1% BSA, pH 7.4, 0.1 mM bacitracin, and 100KIU/ml aprotinin; filtration is carried out using GF/C WHATMAN filters(presoaked in 1.0% polyethyeneimine for 2 hours prior to use); and thefilters are washed twice with 5 mLs cold binding buffer without BSA,bacitracin, or aprotinin.Titer of the passage 3 baculoviral stock is determined by plaque assayand a multiplicity of infection, incubation time course, binding assayexperiment is carried out to determine conditions for optimal receptorexpression.A multiplicity of infection of 0.1 and a 72-hour incubation were thebest infection parameters found for hC5a receptor expression in up to1-liter Sf9 cell infection cultures.

Example 16 Baculoviral Infections

Log-phase Sf9 cells (INVITROGEN Corp., Carlsbad Calif.), are infectedwith one or more stocks of recombinant baculovirus followed by culturingin insect medium at 27° C. Infections are carried out either only withvirus directing the expression of the hC5a receptor or with this virusin combination with three G-protein subunit-expression virus stocks: 1)rat Ga_(i2) G-protein-encoding virus stock (BIOSIGNAL #V5J008), 2)bovine b1 G-protein-encoding virus stock (BIOSIGNAL #V5H012), and 3)human g2 G-protein-encoding virus stock (BIOSIGNAL #V6B003), which maybe obtained from BIOSIGNAL Inc., Montreal.

The infections are conveniently carried out at a multiplicity ofinfection of 0.1:1.0:0.5:0.5. At 72 hours post-infection, a sample ofcell suspension is analyzed for viability by trypan blue dye exclusion,and the remaining Sf9 cells are harvested via centrifugation (3000rpm/10 minutes/4° C.).

Example 17 Purified Recombinant Insect Cell Membranes

Sf9 cell pellets are resuspended in homogenization buffer (10 mM HEPES,250 mM sucrose, 0.5 ÿg/ml leupeptin, 2 ÿg/ml Aprotinin, 200 ÿM PMSF, and2.5 mM EDTA, pH 7.4) and homogenized using a POLYTRON homogenizer(setting 5 for 30 seconds). The homogenate is centrifuged (536×g/10minutes/4° C.) to pellet the nuclei. The supernatant containing isolatedmembranes is decanted to a clean centrifuge tube, centrifuged(48,000×g/30 minutes, 4° C.) and the resulting pellet resuspended in 30ml homogenization buffer. This centrifugation and resuspension step isrepeated twice. The final pellet is resuspended in ice cold Dulbecco'sPBS containing 5 mM EDTA and stored in frozen aliquots at −80° C. untilneeded. The protein concentration of the resulting membrane preparation(hereinafter “P2 membranes”) is conveniently measured using a Bradfordprotein assay (Bio-Rad Laboratories, Hercules, Calif.). By this measure,a 1-liter culture of cells typically yields 100–150 mg of total membraneprotein.

Example 18 Agonist-Induced GTP Binding

Agonist-stimulated GTP-gamma³⁵S binding (“GTP binding”) activity can beused to identify agonist and antagonist compounds and to differentiateneutral antagonist compounds from those that possess inverse agonistactivity. This activity can also be used to detect partial agonismmediated by antagonist compounds. A compound being analyzed in thisassay is referred to herein as a “test compound.” Agonist-stimulated GTPbinding activity is measured as follows: Four independent baculoviralstocks (one directing the expression of the hC5a receptor and threedirecting the expression of each of the three subunits of aheterotrimeric G-protein) are used to infect a culture of Sf9 cells asdescribed in Example 16.

Agonist-stimulated GTP binding on purified membranes (prepared asdescribed in Example 17) is assessed using hC5a (Sigma Chemical Co., St.Louis, Mo., USA) as agonist in order to ascertain that thereceptor/G-protein-alpha-beta-gamma combination(s) yield a functionalresponse as measured by GTP binding.

P2 membranes are resuspended by Dounce homogenization (tight pestle) inGTP binding assay buffer (50 mM Tris pH 7.0, 120 mM NaCl, 2 mM MgCl2, 2mM EGTA, 0.1% BSA, 0.1 mM bacitracin, 100KIU/mL aprotinin, 5 μM GDP) andadded to reaction tubes at a concentration of 30 ug protein/reactiontube. After adding increasing doses of the agonist hC5a atconcentrations ranging from 10⁻¹² M to 10⁻⁶ M, reactions are initiatedby the addition of 100 pM GTP gamma³⁵S. In competition experiments,non-radiolabeled test compounds (e.g., compounds of the invention) areadded to separate assays at concentrations ranging from 10⁻¹⁰ M to 10⁻⁵M along with 10 nM hC5a to yield a final volume of 0.25 mL.

Neutral antagonists are those test compounds that reduce theC5a-stimulated GTP binding activity towards, but not below, baseline(the level of GTP bound by membranes in this assay in the absence ofadded C5a or other agonist and in the further absence of any testcompound).

In contrast, in the absence of added C5a certain preferred compounds ofthe invention will reduce the GTP binding activity of thereceptor-containing membranes below baseline, and are thus characterizedas inverse agonists. If a test compound that displays antagonistactivity does not reduce the GTP binding activity below baseline in theabsence of the C5a agonist, it is characterized as a neutral antagonist.

An antagonist test compound elevates GTP binding activity above baselinein the absence of added hC5a in this GTP binding assay is characterizedas having partial agonist activity. Preferred antagonist compounds ofthe invention do not elevate GTP binding activity under such conditionsmore than 10% above baseline, preferably not more than 5% abovebaseline, and most preferably not more than 2% above baseline.

Following a 60-minute incubation at room temperature, the reactions areterminated by vacuum filtration over GF/C filters (pre-soaked in washbuffer, 0.1% BSA) followed by washing with ice-cold wash buffer (50 mMTris pH 7.0, 120 mM NaCl). The amount of receptor-bound (and therebymembrane-bound) GTP gamma³⁵S is determined by measuring the boundradioactivity, preferably by liquid scintillation spectrometry of thewashed filters. Non-specific binding is determined using 10 mM GTP gamma³⁵S and typically represents less than 5 percent of total binding. Datais expressed as percent above basal (baseline). The results of these GTPbinding experiments may be conveniently analyzed using SIGMAPLOTsoftware (SPSS Inc., Chicago, Ill., USA).

Example 19 Calcium Mobilization Assays

A. Response to C5a

U937 cells are grown in differentiation media (1 mM dibutyrl cAMP inRPMI 1640 medium containing 10% fetal bovine serum) for 48 hrs at 37 Cthen reseeded onto 96-well plates suitable for use in a FLIPR™ PlateReader (Molecular Devices Corp., Sunnyvale Calif.). Cells are grown anadditional 24 hours (to 70–90% confluence) before the assay. The cellsare then washed once with Krebs Ringer solution. Fluo-3 calciumsensitive dye (Molecular Probes, Inc. Eugene, Oreg.) is added to 10ug/mL and incubated with the cells at room temperature for 1 to 2 hours.The 96 well plates are then washed to remove excess dye. Fluorescenceresponses, measured by excitation at 480 nM and emission at 530 nM, aremonitored upon the addition of human C5a to the cells to a finalconcentration of 0.01–30.0 nM, using the FLIPR™ device (MolecularDevices). Differentiated U937 cells typically exhibit signals of5,000–50,000 Arbitrary Fluorescent Light Units in response to agoniststimulation.

B. Assays for Determination of ATP Responses

Differentiated U937 cells (prepared and tested as described above under“A. Response to C5a”) are stimulated by the addition of ATP (rather thanC5a) to a final concentration of 0.01 to 30 uM. This stimulationtypically triggers a signal of 1,000 to 12,000 arbitrary fluorescencelight units. Certain preferred compounds of the invention produce lessthan a 10%, preferably less than a 5%, and most preferably less than a2% alteration of this calcium mobilization signal when this controlassay is carried out in the presence or absence of the compounds.

C. Assays for the Identification of Receptor Modulatorv Agents:Antagonists and Agonists

Those of skill in the art will recognize that the calcium mobilizationassay described above may be readily adapted for identifying testcompounds as having agonist or antagonist activity, at the human C5areceptor.

For example, in order to identify antagonist compounds, differentiatedU937 cells are washed and incubated with Fluo-3 dye as described above.One hour prior to measuring the fluorescence signal, a subset of thecells is incubated with a 1 M concentration of at least one compound tobe tested. The fluorescence response upon the subsequent addition of 0.3nM (final concentration) human recombinant C5a is monitored using theFLIPR™ plate reader. Antagonist compounds elicit at least a 2-folddecrease in the fluorescence response relative to that measured in thepresence of human C5a alone. Preferred antagonist compounds elicit atleast a 5-fold, preferably at least a 10-fold, and more preferably atleast a 20-fold decrease in the fluorescence response relative to thatmeasured in the presence of human C5a alone. Agonist compounds elicit anincrease in fluorescence without the addition of C5a, which increasewill be at least partially blocked by a known C5a receptor antagonist.

Example 20 Assays to evaluate agonist activity of small molecule C5areceptor antagonists

Preferred compounds of the invention are C5a receptor antagonists thatdo not possess significant (e.g., greater than 5%) agonist activity inany of the C5a mediated functional assays discussed herein.Specifically, this undesired agonist activity can be evaluated, forexample, in the GTP binding assay of Example 18, by measuring smallmolecule mediated GTP binding in the absence of the natural agonist,C5a. Similarly, in a calcium mobilization assay e.g., that of Example19, a small molecule compound can be directly assayed for the ability ofthe compound to stimulate calcium levels in the absence of the naturalagonist, C5a. The preferred extent of C5a agonist activity exhibited bycompounds of the invention is less than 10%, more preferably less than5% and most preferably less than 2% of the response elicited by thenatural agonist, C5a.

Example 21 Expression of a C5a receptor

A human C5a receptor cDNA was obtained by PCR using 1) a forward primeradding a Kozak ribosome binding site and 2) a reverse primer that addedno additional sequence, and 3) an aliquot of a Stratagene Human FetalBrain cDNA library as template. The sequence of the resulting PCRproduct is set forth as SEQ ID NO: 1. The PCR product was subcloned intothe cloning vector pCR-Script AMP (STR_(A)TAGENE, La Jolla,Calif.) atthe Srf I site. It was then excised using the restriction enzymes EcoRIand NotI and subcloned in the appropriate orientation for expressioninto the baculoviral expression vector pBacPAK 9 (CLONTECH, Palo Alto,Calif.) that had been digested with EcoRI and NotI.

Example 22 Radioligand Binding Assays

Purified P2 membranes, prepared by the method given above, areresuspended by Dounce homogenization (tight pestle) in binding buffer(50 mM Hepes pH. 7.6, 120 mM NaCl, 1 mM CaCl₂, 5 mM MgCl₂, o.1% BSA, pH7.4, 0.1 mM bacitracin, 100 KIU/ml aprotinin).

For saturation binding analysis, membranes (5–50 μg) are added topolypropylene tubes containing 0.005–0.500 nM [¹²⁵I]C5a (human(recombinant), New England Nuclear Corp., Boston, Mass.). Nonspecificbinding is determined in the presence of 300 nM hC5a (Sigma ChemicalCo., St. Louis, Mo.) and accounted for less than 10% of total binding.For evaluation of guanine nucleotide effects on receptor affinity, GTPySis added to duplicate tubes at the final concentration of 50 μM.

For competition analysis, membranes (5–50 μg) are added to polypropylenetubes containing 0.030 nM [¹²⁵I]C5a (human). Non-radiolabeled displacersare added to separate assays at concentrations ranging from 10⁻¹⁰ M to10⁻⁵ M to yield a final volume of 0.250 mL. Nonspecific binding isdetermined in the presence of 300 nM hC5a (Sigma Chemical Co., St.Louis, Mo.) and accounted for less than 10% of total binding. Followinga 2-hour incubation at room temperature, the reaction is terminated byrapid vacuum filtration. Samples are filtered over presoaked (in 1.0%polyethyleneimine for 2 hours prior to use) GF/C WHATMAN filters andrinsed 2 times with 5 mLs cold binding buffer without BSA, bacitracin,or aprotinin. Remaining bound radioactivity is quantified by gammacounting. K_(i) and Hill coefficient (“nH”) are determined by fittingthe Hill equation to the measured values with the aid of SIGMAPLOTsoftware.

As set forth in the tables appended hereto, R groups do not necessarilycorrelate with those R groups shown in the text of the specification orin the claims.

The following table 1 (214–323) is a list of preferred 1,2,5 substitutedimidazoles of the present invention;

The following table 2 (324–429) is a list of preferred 1,2,4,5substituted imidazoles of the present invention;

The following table 3 (430–431) is a list of preferred pyrazoles of thepresent invention;

The following table 4 (432–433) is another list of preferred 1,2,4,5substituted imidazoles of the present invention;

The following table 5 (434–464) is a list of preferred amides of thepresent invention; and

The following table 6 (456–468) is a list of preferred amides of thepresent invention.

Additional Aspects of Preferred Compounds of the Invention

The most preferred compounds of the invention are suitable forpharmaceutical use in treating human patients. Accordingly, suchpreferred compounds do not exhibit single or multiple dose acute orlong-term toxicity, mutagenicity (e.g., as determined in a bacterialreverse mutation assay such as an Ames test), teratogenicity,tumorogenicity, or the like, and rarely trigger adverse effects (sideeffects) when administered at therapeutically effective dosages. Forexample, preferred compounds of the invention will not prolong heart QTintervals (e.g., as determined by electrocardiography, e.g., in guineapigs, minipigs or dogs). Therapeutically effective doses orconcentrations of such compounds do not cause liver enlargement when fedto or injected into laboratory animals (e.g., mice or rats) and do notpromote the release of liver enzymes (e.g., ALT, LDH, or AST) fromhepatocytes in vitro or in vivo.

Because side effects are often due to undesirable receptor activation orantagonism, preferred compounds of the invention exert theirreceptor-modulatory effects with high specificity. This means that theyonly bind to, activate, or inhibit the activity of certain receptorsother than C5a receptors with affinity constants of greater than 100nanomolar, preferably greater than 1 micromolar, more preferably greaterthan 10 micromolar and most preferably greater than 100 micromolar. Suchreceptors preferably are selected from neurotransmitter receptors suchas alpha- or beta-adrenergic receptors, muscarinic receptors(particularly m1, m2, or m3 receptors), dopamine receptors, andmetabotropic glutamate receptors; and also include histamine receptorsand cytokine receptors, e.g., interleukin receptors, particularly IL-8receptors. Such receptors may also include GABAA receptors, bioactivepeptide receptors (other than C5a receptors, including NPY or VIPreceptors), neurokinin receptors, bradykinin receptors, hormonereceptors (e.g., CRF receptors, thyrotropin releasing hormone receptors,or melanocyte-concentrating hormone receptors).

Additionally, preferred compounds of the invention do not inhibit orinduce microsomal cytochrome P450 enzyme activities, such as CYP1A2activity, CYP2A6 activity, CYP2C₉ activity, CYP2C₁₉ activity, CYP2D6activity, CYP2E1 activity, or CYP3A4 activity. Preferred compounds ofthe invention also do not exhibit cytotoxicity in vitro or in vivo, arenot clastogenic, e.g., as determined using a mouse erythrocyte precursorcell micronucleus assay, an Ames micronucleus assay, a spiralmicronucleus assay, or the like and do not induce sister chromatidexchange, e.g., in Chinese hamster ovary cells.

Highly preferred C5a receptor antagonist compounds of the invention alsoinhibit the occurrence of C5a-induced oxidative burst (OB) ininflammatory cells, e.g., neutrophil, as can be conveniently determinedusing an in vitro neutrophil OB assay.

Initial characterization of preferred compounds of the invention can beconveniently carried out using a C5a receptor binding assay orfunctional assay, such as set forth in the Examples, and may beexpedited by applying such assays in a high throughput screeningsetting.

The foregoing description is illustrative thereof, and it understoodthat variations and modification can be effected without departing fromthe scope or spirit of the invention as set forth in the followingclaims.

TABLE 1

CMP # R1 R2 R3 R4 R5 Rtn Time Cmd Mass H+ Ion Obs 200

1.95 448.2627 449.3036 201

1.96 462.2784 463.3201 202

1.91 462.2784 463.3241 203

2.09 459.2675 460.3053 204

2.1 459.2675 460.2983 205

2.04 467.2573 468.2888 206

2.05 481.2729 482.3052 207

2 467.2573 468.2885 208

1.96 453.2416 454.2695 209

1.9 375.2675 376.2897 210

2 453.2416 454.2688 211

1.9 434.247 435.2789 212

1.92 492.2525 493.2912 213

1.94 469.2729 470.2986 214

1.97 497.2314 498.2636 215

2.06 473.3042 474.3346 216

2.03 445.2729 446.302 217

2.1 477.258 478.2953 218

2.01 485.2479 486.2815 219

2.01 471.2322 472.266 220

1.8 438.2784 439.3118 221

1.78 438.2784 439.313 222

1.86 452.294 453.3306 223

2.08 459.2886 460.3148 224

1.99 459.1981 460.226 225

1.86 419.2573 420.2867 226

1.79 405.2416 406.2684 227

2.08 521.1637 522.2009 228

1.91 513.2628 514.2951 229

2.02 461.2467 462.2794 230

2. 461.2467 462.2892 231

2.05 465.2239 466.267 232

2.1 477.1739 478.2021 233

1.98 462.2784 463.3135 234

235

2.07 535.1793 536.2415 236

2.11 495.2886 496.3355 237

238

2 483.2522 484.3027 239

1.87 482.3046 483.3743 240

1.98 527.242 528.2967 241

1.85 482.3046 483.3671 242

2.01 483.2522 484.3157 243

1.87 482.3046 483.3743 244

1.98 515.222 516.2815 245

2.01 467.2573 468.3038 246

2 511.2471 512.3024 247

1.99 471.2322 472.2836 248

1.98 515.222 516.2795 249

2.01 483.2522 484.3008 250

2.06 503.2573 504.3187 251

2.08 477.258 478.3242 252

1.95 496.2838 497.3316 253

1.93 496.2838 497.3374 254

1.99 439.2624 440.3063 255

2.05 487.2027 488.258 256

2.1 443.1895 444.2521 257

2 439.2624 440.3058 258

1.78 504.2525 505.3246 259

1.97 459.2077 460.287 260

2.06 477.1739 478.2339 261

2.06 461.2034 462.2581 262

263

1.78 480.3253 481.4043 264

1.75 410.247 411.2961 265

2.01 503.2339 504.2863 266

2.07 493.2341 494.2973 267

1.88 425.2467 426.2948 268

2.05 443.2128 444.2672 269

2.04 461.2034 462.255 270

2.1 477.1739 478.2429 271

2.06 521.1637 522.2083 272

2.02 479.2573 480.2964 273

2.03 433.2729 434.3264 274

1.9 433.2729 434.3161 275

1.74 424.2627 425.298 276

1.98 454.2369 455.2756 277

2.09 495.1644 496.227 278

1.86 470.2846 471.3502 279

2.07 496.3002 497.375 280

2.02 487.2027 488.2712 281

2.02 501.2183 502.2874 282

283

2.01 459.2886 460.3366 284

2 473.3042 474.3561 285

2.1 465.3144 466.3706 286

287

1.99 503.2784 504.3394 288

289

1.99 459.2886 460.3446 290

2.07 447.2886 448.3387 291

2.06 481.2729 482.3294 292

2.08 475.3199 476.3839 293

2.11 473.3042 474.361 294

1.76 417.2416 418.2879 295

2.05 423.2675 424.2875 296

2.06 467.2573 468.2819 297

2.01 413.2831 414.3154 298

2.05 467.2573 468.2849 299

2.02 451.2624 452.2898 300

2.02 477.1983 478.2289 301

2.01 477.1983 478.2308 302

1.95 495.2522 496.3082 303

1.99 529.2377 530.2964 304

2.01 485.2479 486.3004 305

2.05 277.2791 478.3398 306

307

1.99 491.214 492.2748 308

1.91 425.2234 426.2757 309

1.69 425.2579 426.3054 310

1.96 503.1879 504.2485 311

1.98 459.1981 460.2525 312

1.99 451.2293 452.2899 313

1.99 469.2529 470.3111 314

2.01 483.2686 484.3253 315

1.78 512.3315 513.4124 316

1.81 432.3253 433.3902 317

1.83 450.3159 451.3883 318

1.97 506.2682 507.3284 319

1.95 503.1976 504.2582 320

1.97 535.2038 536.2633 321

1.93 493.2729 494.3287 322

2.06 491.214 492.2753 323

2.02 471.2453 472.317 324

1.92 443.214 444.2721 325

1.98 457.2296 458.2892 326

1.97 457.2296 458.2943 327

1.87 449.2842 450.3473 328

2.1 475.1957 476.2632 329

2.02 423.2675 424.3092 330

331

1.98 491.214 492.2755 332

1.99 491.214 492.2755 333

2.02 547.2635 548.3262 334

2.08 577.1729 578.25 335

1.96 511.2471 512.298 336

1.95 517.2132 518.2731 337

2.15 521.3173 522.3696 338

2.15 515.3512 516.4249 339

1.88 483.2522 484.3056 340

2.05 487.3563 488.4303 341

2.08 515.3512 516.4047 342

2.05 501.3719 502.4088 343

1.97 467.2573 468.2854 344

1.94 433.2729 434.297 345

2.07 473.3042 474.3316 346

2.01 459.2886 460.3174 347

1.88 439.2624 440.2939 348

1.7 405.278 406.3116 349

1.96 445.3093 446.3387 350

2.07 523.3199 524.3464 351

2.04 489.3355 490.3575 352

2.15 529.3668 530.3951 353

2.01 509.3042 510.337 354

2.08 515.3512 516.3834 355

356

357

2.07 501.3719 502.3938 358

2.08 539.3148 540.3187 359

2.04 505.3304 506.3531 360

2.16 545.3618 546.3911 361

2 483.2522 484.2723 362

1.93 449.2679 450.2899 363

2.08 489.2991 490.3192 364

2.06 525.2991 526.36 365

2.12 531.3461 532.3955 366

1.95 469.2365 470.2861 367

1.8 435.2622 436.2889 368

2.03 475.2835 476.3151 369

1.94 511.3199 512.3583 370

1.72 477.3355 478.3816 371

1.98 517.3668 518.4061 372

2.02 553.3304 554.3617 373

1.96 519.3461 520.382 374

2.09 559.3774 560.4091 375

1.92 497.2679 498.3003 376

2 503.3148 504.343 377

378

2 525.3355 526.3682 379

1.81 491.3512 492.3873 380

2.05 531.3825 532.415 381

382

1.94 475.3199 476.3517 383

1.86 483.2522 484.2405 384

1.94 517.2132 518.2035 385

1.97 497.2679 498.2453 386

1.95 511.2471 512.2275 387

2.06 553.2941 554.2728 388

2.05 519.3097 520.2906 389

2.13 559.341 560.3246 390

1.78 469.2365 470.2381 391

1.88 503.1976 504.1985 392

1.89 483.2522 484.2435 393

1.89 497.2314 498.227 394

1.71 455.2573 456.2579 395

1.84 489.2183 490.22 396

1.85 469.2729 470.2647 397

1.85 483.2522 484.24 398

1.97 531.3825 532.3688 399

2.07 509.3042 510.2987 400

1.99 481.3093 482.3098 401

2.05 515.2703 516.2676 402

2.01 481.3093 482.3063 403

2.03 523.3199 524.3068 404

2.04 523.3199 524.3074 405

1.96 475.3199 476.3177 410

2.01 489.3355 490.3296 411

2.08 495.325 496.3224 412

1.92 461.3406 462.3352 413

2.15 501.3719 502.3614 406

1.79 447.325 448.3324 407

2.02 481.286 482.2877 408

1.88 447.325 448.326 409

1.97 489.3355 490.3298 414

2.1 515.3124 516.3123 415

2.08 495.325 496.3181 416

2.01 461.3400 462.3389 417

2.16 501.3719 502.3629 418

419

420

2.08 514.4036 515.423 421

2.14 515.3512 516.3379 422

2.14 521.3173 522.3266 423

TABLE 1A

R3 is H unless otherwise specified Rtn H+ CMP # R1 R2 R3 R4 R5 Time CmdMass Ion Obs 424

2.02 427.2424 428.2541 425

2.06 441.258 442.2744 426

2.1 455.2737 456.2899 427

2.08 455.2737 456.2953 428

2.13 469.2893 470.3137 429

2.02 485.2479 486.2833 430

2.15 481.3093 482.332 431

432

1.98 419.2573 420.2856 433

1.91 431.2573 432.2898 434

1.92 433.2729 434.3079 435

1.91 433.2729 434.3078 436

2.04 433.2729 434.3079 437

2.04 401.2831 402.3126 438

2.01 445.2729 446.3118 439

1.99 447.2886 448.329 440

1.98 447.2886 448.3293 441

1.95 447.2886 448.3331 442

2.06 447.2886 448.3315 443

2.09 403.2987 404.3406 444

2.07 447.2886 448.3385 445

1.99 459.2886 460.3416 446

2.07 459.2886 460.3427 447

2.04 461.3042 462.362 448

2.04 473.3042 474.3634 449

2.12 473.3042 474.3605 450

2.05 473.3042 474.3627 451

2.09 475.3199 476.3831 452

2.09 529.2729 530.334 453

2.09 545.2678 546.3349 454

2.02 423.2675 424.3183 455

2.01 409.2518 410.3021 456

2.07 459.2675 460.326 457

2 453.2416 454.3023 458

2.06 437.2831 438.3368 459

2.05 423.2675 424.318 460

2.11 473.2831 474.3436 461

2.04 467.2573 468.3188 462

2.06 437.2831 438.3386 463

464

2.11 473.2831 474.3485 465

2.03 467.2573 468.3192 466

2.04 423.2675 424.3211 467

2.1 473.2831 474.3467 468

2.02 467.2573 468.3227 469

1.99 471.2322 472.3021 470

2.02 441.258 442.3175 471

1.98 471.2322 472.3026 472

2.03 441.258 442.3185 473

2.01 427.2424 428.3031 474

2.07 477.258 478.3228 475

1.99 471.2322 472.3008 476

2.1 451.2987 452.3606 477

2.08 437.2831 438.351 478

2.14 487.2987 488.3652 479

2.07 481.2729 482.3446 480

2.08 451.2987 452.3621 481

2.08 437.2831 438.346 482

2.14 487.2987 488.3646 483

2.06 481.2729 482.3413 484

2.09 437.2831 438.3447 485

2.07 481.2729 482.3401 486

2.09 451.2987 452.3614 487

2.08 437.2831 438.3399 488

2.06 481.2729 482.3407 489

2.11 451.2987 452.3647 490

2.09 437.2831 438.3419 491

2.14 487.2987 488.3654 492

2.07 481.2729 482.3416 493

2.1 451.2987 452.3654 494

2.09 437.2831 438.3447 495

2.14 487.2987 488.3656 496

2.07 481.2729 482.3421 497

2.02 453.278 454.3456 498

2.01 439.2624 440.3276 499

2.06 489.278 490.3461 500

1.99 483.2522 484.3252 501

2 453.278 454.3479 502

1.99 439.2624 440.332 503

2.06 489.278 490.3477 504

1.97 483.2522 484.3253 505

1.96 453.278 454.3445 506

1.99 439.2624 440.3253 507

2.07 489.278 490.3457 508

1.97 483.2522 484.3227 509

2.07 455.2737 456.3386 510

2.06 441.258 442.3267 511

2.11 491.2737 492.3441 512

2.04 485.2479 486.3185 513

2.04 441.258 442.3253 514

2.03 485.2479 486.3174 515

2.05 455.2737 456.3376 516

2.04 441.258 442.325 517

2.1 491.2737 492.3412 518

2.02 485.2479 486.3193 519

2.04 487.2027 488.2782 520

2.12 493.2285 494.3027 521

2.04 487.2027 488.2797 522

2.06 457.2285 458.2941 523

2.04 443.2128 444.2792 524

2.09 493.2285 494.3003 525

2.03 487.2027 488.278 526

2 489.2228 490.2792 527

2.02 445.2329 446.2807 528

2.06 495.2486 496.2982 529

2 489.2228 490.2744 530

2.01 445.2329 446.282 531

2.07 495.2486 496.2984 532

1.99 489.2228 490.2794 533

2.08 495.2486 496.3038 534

2 489.2228 490.2825 535

2.14 465.3144 466.3682 536

2.13 451.2987 452.3522 537

2.19 501.3144 502.3722 538

2.11 495.2886 496.3486 539

2.12 451.2987 452.3553 540

2.16 501.3144 502.3736 541

2.1 495.2886 496.3533 542

2.05 467.2937 468.352 543

2.04 453.278 454.334 544

2.1 503.2937 504.355 545

2.02 497.2679 498.3338 546

2.1 503.2937 504.3604 547

2.01 497.2679 498.336 548

2.02 467.2937 468.3528 549

2.01 497.2679 498.3345 550

1.99 467.2573 468.3251 551

2.05 503.2573 504.3299 552

1.97 497.2314 498.303 553

2.05 469.2552 470.3185 554

2.05 455.2395 456.3164 555

2.1 505.2552 506.3273 556

2.03 499.2293 500.3005 557

1.99 471.2686 472.3348 558

1.98 457.2529 458.3177 559

2.05 507.2686 508.3424 560

1.96 501.2428 502.3192 561

2.1 457.2285 458.2933 562

2.14 507.2441 508.3201 563

2.08 501.2183 502.2952 564

2.04 505.1932 506.2737 565

2.17 465.3144 466.3809 566

2.15 509.3042 510.3789 567

2.15 479.33 480.3981 568

2.14 465.3144 466.3795 569

2.13 509.3042 510.383 570

2.06 511.2835 512.3632 571

2.06 467.2937 468.3609 572

2.12 517.3093 518.3871 573

2.04 511.2835 512.3613 574

2.1 483.2708 484.3423 575

2.08 469.2552 470.3222 576

2.13 519.2708 520.3477 577

2.06 513.245 514.3214 578

2.02 481.2141 482.2788 579

2 525.2039 526.2794 580

2.08 513.2392 514.3017 581

2 507.2133 508.2841 582

2.06 513.2392 514.3171 583

1.98 507.2133 508.2843 584

2.03 461.2034 462.2718 585

2.08 611.2101 612.2986 586

2.01 505.1932 506.2769 587

2.17 561.1505 562.2524 588

1.99 527.2784 528.3599 589

2.02 459.2486 460.326 590

2.01 503.2384 504.3166 591

2.06 469.2552 470.3206 592

2.03 513.245 514.321 593

2 467.2573 468.3217 594

1.97 511.2471 512.3246 595

2.07 533.1904 534.271 596

2.09 501.1779 502.2356 597

2.08 545.1678 546.2542 598

2.04 553.2496 554.1792 599

2.07 545.1678 546.1213 600

2.05 555.1901 556.1432 601

2.05 597.1991 598.16 602

2.04 455.2395 456.2075 603

2.01 499.2293 500.2002 604

1.99 605.1889 606.17 605

2.06 575.1783 576.16 606

2.09 573.2991 574.2837 607

1.97 527.2784 528.259 608

2 503.2384 504.2233 609

2.1 559.2835 560.2635 610

2.1 593.1539 594.1388 611

2.07 593.1539 594.146 612

1.99 467.2573 468.2505 613

2.02 473.2137 474.2052 614

2.03 481.2729 482.2651 615

2.03 481.2729 482.2703 616

2.05 437.2831 438.2783 617

2.03 481.2729 482.2692 618

1.98 483.2522 484.2532 619

2 485.2479 486.2474 620

2.08 451.2987 452.2939 621

2.07 495.2886 496.2867 622

2.08 451.2987 452.2961 623

624

625

1.99 497.2679 498.2035 626

2.02 497.2479 498.1985 627

2.02 511.2835 512.236 628

2.04 511.2835 512.2421 629

2.03 497.2679 498.2339 630

1.98 513.2628 514.2338 631

2.11 545.3042 546.2813 632

1.99 539.2784 540.2627 633

2.01 509.3042 510.2987 634

2.11 545.3042 546.2994 635

2.01 539.2784 540.2756 636

2.06 547.2447 548.2516 637

638

2.09 527.1936 528.22 639

640

1.99 441.2239 442.2316 641

2.09 491.2395 492.2484 642

1.97 485.2137 486.2251 643

2.07 475.2624 476.2701 644

1.95 469.2365 470.2487 645

2.11 521.3042 522.3236 646

2.01 463.2987 464.304 647

2.02 449.2831 450.2887 648

1.99 493.2729 494.2809 649

2.06 453.258 454.2635 650

2.11 503.2737 504.279 651

2.05 497.2479 498.2578 652

2.05 457.2285 458.2423 653

2.03 501.2183 502.2353 654

2.13 465.3144 466.33 655

2.1 509.3042 510.315 656

2.04 467.2937 468.3029 657

2.02 511.2835 512.2963 658

2.06 467.2937 468.3049 659

2.04 511.2835 512.2961 660

2.07 481.3093 482.3199 661

2.05 525.2991 526.3086 662

2.01 483.2886 484.3015 663

1.98 527.2784 528.3032 664

2.03 535.2447 536.2623 665

2.16 535.3199 536.342 666

667

2.07 543.2886 544.3081 668

669

670

671

2.19 549.3355 550.3612 672

1.95 513.2628 514.2707 673

674

1.96 513.2628 514.2808 675

676

2.03 517.2132 518.2341 677

678

2.09 501.1779 502.2102 679

680

2.11 515.1936 516.229 681

682

2.15 551.1936 552.23 683

684

2.08 545.1678 546.202 685

686

687

688

2.13 557.3042 558.3334 689

690

2.07 535.1484 536.1722 691

692

2.06 579.1383 580.1661 693

694

2.07 535.1484 536.1789 695

696

2.05 579.1383 580.1685 697

698

2.04 579.1383 580.1639 699

700

701

702

703

704

2.08 531.2089 532.2461 705

706

2.07 531.2089 532.2447 707

708

2.12 601.194 602.24 709

710

1.84 437.2479 438.2715 711

1.97 437.2479 438.2693 712

1.9 449.2479 450.2746 713

1.91 451.2635 452.2936 714

1.91 451.2635 452.2922 715

2.02 451.2635 452.2937 716

2 463.2635 464.2918 717

1.98 465.2791 466.3056 718

1.97 465.2791 466.3057 719

1.94 465.2791 466.3067 720

2.05 465.2791 466.31 721

2.06 465.2791 466.309 722

1.99 477.2791 478.3101 723

2.06 477.2791 478.3092 724

2.03 479.2948 480.3289 725

2.03 491.2948 492.327 726

2.1 491.2948 492.3293 727

2.04 491.2948 492.3288 728

2.08 493.3105 494.3472 729

2.06 465.2791 466.3023 730

2.08 465.2791 466.3028 731

1.99 477.2791 478.3062 732

2.07 477.2791 478.3031 733

2.04 479.2948 480.323 734

1.99 471.2322 472.2518 735

2.03 485.2479 486.2677 736

2.05 485.2479 486.2654 737

2.12 447.305 448.3199 738

1.99 489.2228 490.2399 739

740

2.05 499.2635 500.2832 741

2.14 461.3206 462.3372 742

2.04 499.2635 500.2898 743

1.9 451.2635 452.2902 744

1.96 515.222 516.245 745

2.06 477.2791 478.3002 746

2.03 517.2199 518.246 747

2.08 433.2893 434.3055 748

1.96 421.2893 422.306 749

2.11 447.305 448.3214 750

1.99 435.305 436.3263 751

2.05 463.2999 464.3266 752

2.05 449.3206 450.3442 753

2.04 449.3206 450.3435 754

2.18 475.3363 476.3594 755

1.91 451.2635 452.2869 756

1.97 515.222 516.2496 757

2.08 477.2791 478.3031 758

1.99 453.2614 454.2874 759

2.02 517.2199 518.2543 760

2.1 463.3363 464.3699 761

2.03 467.277 468.306 762

1.98 531.2534 532.2854 763

1.97 531.2534 532.2903 764

1.93 531.2534 532.285 765

2.06 539.1542 540.1926 766

2.04 549.1427 550.1876 767

2.04 549.1427 550.1861 768

2.03 549.1427 550.1867 769

2.13 575.2948 576.329 770

771

772

773

2.02 465.3144 466.3379 774

2.01 463.3144 466.3359 775

2.06 465.3144 466.3358 776

1.99 525.2039 526.2423 777

1.99 525.2039 526.2429 778

1.93 545.269 546.3107 779

536.3018 780

2.07 535.2835 536.3018 781

2.09 555.2356 556.2706 782

1.97 531.2534 532.2892 783

1.94 531.2534 532.2867 784

2 471.2453 472.2802 785

2 523.321 524.354 786

2.03 499.2635 500.2993 787

1.98 515.2584 516.2964 788

1.98 515.2584 516.2967 789

2.03 519.2089 520.2536 790

1.99 515.2584 516.2904 791

1.98 515.2584 516.3315 792

2.06 611.1445 612.2336 793

2.05 563.1584 564.26 794

2.03 531.2356 532.3217 795

2.06 611.1445 612.2438 796

2.02 531.2356 532.3212 797

2.03 561.245 562.3386 798

1.74 436.3002 437.386 799

1.88 462.3159 463.4108 800

1.87 462.3159 463.4136 801

1.97 507.2133 508.3045 802

2.01 517.2199 518.3113 803

2.02 555.2145 556.3143 804

2.02 667.2281 668.3466 805

2.06 563.1584 564.27 806

2.06 551.181 552.2875 807

2.03 521.2479 522.3456 808

2.09 559.2635 560.3663 809

2.03 473.2301 474.313 810

2.02 517.2199 518.3132 811

2.01 501.2558 502.358 812

2.09 527.2715 528.3815 813

2.05 521.2479 522.3471 814

815

2.09 455.2504 456.3523 816

2.07 519.2089 520.3145 817

1.85 449.2842 450.3776 818

1.95 513.2428 514.3442 819

2.04 475.2999 476.4023 820

1.98 537.2239 538.3297 821

2.04 457.2893 458.3844 822

823

824

1.96 513.2428 514.345 825

2.04 475.2999 476.3996 826

1.97 473.2654 474.3578 827

2.08 499.281 500.3929 828

829

2.08 577.274 578.3961 830

2 503.2384 504.3399 831

1.99 515.2584 516.3593 832

2.03 529.274 530.3805 833

2.03 563.1584 564.2842 834

1.98 545.269 546.3808 835

1.97 545.269 546.374 836

1.98 545.269 546.3859 837

1.92 545.269 546.3798 838

1.96 559.2846 560.3983 839

2.05 535.2635 536.3757 840

2.04 592.285 593.4103 841

842

2.01 544.2308 545.3511 843

1.88 547.2026 548.3105 844

1.9 549.2228 550.3254 845

1.97 525.2592 526.3528 846

1.94 577.2132 578.3243 847

2.01 553.2496 554.3531 848

1.92 581.229 582.3329 849

1.95 551.1531 552.2697 850

1.95 581.1637 582.2848 851

2.03 557.2001 558.311 852

1.9 591.1522 592.27 853

2.02 617.3042 618.4236 854

1.92 639.1383 640.2621 855

1.95 607.2238 608.3556 856

1.92 621.1627 622.29 857

1.96 651.1733 652.31 858

1.93 657.1288 658.2678 859

1.95 605.1678 606.29 860

2.02 581.2042 582.32 861

1.96 593.1904 594.3127 862

1.97 615.1901 616.3185 863

2.04 591.2264 592.3466 864

1.93 578.2682 579.3848

TABLE 2

H+ CMP Rtn. Cmd. Ion # R1 R2 R3 R4 R5 R6 Time Mass Obs 900

X₃—Br

1.99 453.1779 456.2343 901

X₃—Br

902

X₃—Cl

1.96 409.2285 410.2904 903

1.98 451.2987 452.3564 904

X₃—CH₃

1.91 389.2831 390.327 905

2.06 515.2703 516.3389 906

2.02 501.2547 502.3203 907

2.05 535.239 536.3062 908

1.95 495.2886 496.338 909

1.95 509.3042 510.349 910

2.06 543.2886 544.3537 911

2.06 529.2729 530.3288 912

2.06 527.2936 528.3539 913

1.91 493.3093 494.3662 914

1.98 501.278 502.3292 915

2.04 481.286 482.3375 916

2.06 509.3042 510.3504 917

2.04 533.2941 544.3566 918

2.01 599.2602 560.3214 919

1.98 599.2602 560.3226 920

2.07 515.2936 516.3561 921

1.8 467.2937 466.3449 922

1.97 486.255 487.3133 923

1.96 520.2394 521.3087 924

1.77 521.3519 522.4169 925

1.79 555.3362 566.421 926

2.06 565.2496 566.3239 927

1.76 545.3155 546.3849 928

2.02 531.2563 532.3318 929

1.79 497.3042 498.3625 930

1.95 525.2991 526.3686 931

1.74 511.3311 512.3882 932

2 531.2886 532.3475 933

2 469.2893 470.3573 934

2.03 519.2452 520.3179 935

2.05 553.2296 554.3043 936

1.97 513.2792 514.3508 937

2.06 547.2635 548.3326 938

1.71 483.2886 484.3469 939

1.86 423.2675 424.3207 940

1.94 458.2504 459.2958 941

1.93 492.2378 493.2848 942

1.74 437.3049 466.3629 943

1.92 437.2831 438.2847 944

1.77 495.3362 496.4057 945

1.74 481.3206 482.3854 946

1.76 525.3467 526.4145 947

1.98 481.2729 482.3188 948

2.01 501.278 502.3374 949

1.99 501.278 502.3323 950

1.88 467.2937 468.3544 951

1.88 467.2937 468.352 952

2.04 543.2886 544.3618 953

2.03 509.3042 510.364 954

1.93 536.294 537.3635 955

1.94 502.3097 503.3694 956

2.05 542.3409 543.4108 957

1.92 481.3093 482.3674 958

1.99 529.2729 530.3309 959

1.97 495.2886 496.3324 960

2.08 535.3199 536.3663 961

1.93 502.3097 503.3532 962

2.06 542.3409 543.387 963

1.77 559.3311 560.4 964

1.77 529.3206 530.373 965

966

1.94 528.3253 529.3721 967

1.88 494.3409 495.3921 968

2.05 534.3723 535.461 969

1.77 491.3049 492.3542 970

2.03 568.2661 569.3215 971

1.98 534.2817 535.3365 972

2.14 574.313 575.38 973

1.94 542.3049 543.3302 974

1.89 507.3202 509.3457 975

1.91 522.3359 523.3574 976

2.03 562.3672 563.3868 977

1.96 515.2936 516.3203 978

1.86 481.3093 482.3423 979

2.05 521.3406 522.3415 980

2.06 515.2936 516.3033 981

1.89 481.3093 482.3204 982

2.12 521.3406 522.3559 983

2.06 515.2936 516.3141 984

1.99 481.3093 482.3264 985

2.15 521.3406 522.3597 986

2.03 489.3355 490.3545 987

1.93 461.3406 462.3651 988

2.1 549.3355 550.3556 989

1.99 559.2835 560.3169 990

2.06 565.3304 566.3608 991

1.98 545.3042 546.332 992

1.82 511.3199 512.3492 993

2.05 551.3512 552.3806 994

1.91 488.3515 489.3748 995

2.02 546.2631 547.2886 996

2 512.2787 513.3031 997

2.11 522.3101 553.335 998

2.02 546.2631 547.2888 999

2.03 512.2787 513.3018 1000

2.11 552.3101 553.3454 1001

2.06 578.4349 579.501 1002

2.14 318.4661 619.54 1003

1.71 552.3828 553.43 1004

1.92 592.4141 593.47 1005

1.9 474.3359 475.3617 1006

1.81 558.2995 559.3615 1007

1.78 460.3566 461.4005 1008

2.03 543.2886 544.3141 1009

1.95 509.3042 510.3276 1010

2.08 549.3355 550.3668 1011

1.96 515.2936 516.3184 1012

1.84 481.3093 482.3309 1013

1.98 521.3406 522.3765 1014

1.88 564.2559 565.3013 1015

1.87 530.2715 531.3078 1016

1.88 511.3199 512.3484 1017

1.98 547.301 548.3231 1018

1.96 523.3199 524.3481 1019

1.82 489.3355 490.3575 1020

1.9 509.3042 510.3383 1021

1.88 495.325 496.3488 1022

1.77 461.3406 462.3634 1023

2.03 573.2628 574.2927 1024

2.03 587.2784 588.3088 1025

1.96 573.2628 574.3035 1026

1027

1.85 544.2872 545.3313 1028

2.03 543.2886 544.3122 1029

2.03 509.3042 510.3173 1030

2.12 549.3355 550.3542 1031

1.98 529.2729 530.2999 1032

2.08 535.3199 536.3453 1033

1.97 515.2936 516.3203 1034

1.87 481.3093 482.3294 1035

2.06 559.2835 560.311 1036

2.03 525.2991 526.3195 1037

2.17 565.3304 566.35 1038

1039

2.12 551.3148 552.3455 1040

1.93 531.2886 532.3281 1041

1.74 497.3042 498.3471 1042

1.99 537.3355 538.3746 1043

1.91 572.2787 573.3109 1044

1.88 494.3046 495.3434 1045

1.91 572.2821 573.3249 1046

1047

1048

2.04 595.2777 596.3219 1049

1.85 588.3231 589.3849 1050

1.72 554.3621 555.4208 1051

2 547.301 548.3278 1052

1.78 582.357 583.4136 1053

1.99 573.2991 574.3322 1054

1.95 539.3148 540.3422 1055

2.1 579.3461 580.3743 1056

1.97 545.3042 546.3319 1057

1.81 511.3199 512.3505 1058

2.04 551.3512 552.3825 1059

1.93 606.2665 607.3164 1060

1.91 528.2889 529.3276 1061

1062

1.98 527.2971 508.3281 1063

2.09 561.2814 562.3166 1064

1.87 608.2457 609.2976 1065

1066

1.9 572.2821 573.3206 1067

1.79 580.2508 581.3011 1068

1.9 650.2563 651.3043 1069

1.92 606.2665 607.2383 1070

1.9 650.2563 651.2313 1071

1.96 520.2838 521.3221 1072

1.88 602.2927 603.3342 1073

1.93 631.3192 632.3643 1074

1.78 552.3464 553.3979 1075

1.9 582.3206 583.3616 1076

1.95 534.2995 535.3354 1077

1.99 571.3311 572.3079 1078

1.75 574.2978 575.2848 1079

1.97 614.329 615.3132 1080

1.97 587.2784 588.2736 1081

1.78 608.2457 609.2491 1082

2.03 531.2653 532.2452 1083

1.97 525.2991 526.2742 1084

1.98 525.2991 529.2836 1085

1.82 588.3134 589.3152 1086

1.93 511.3199 512.2905 1087

2.06 565.2496 566.2386 1088

2.07 559.2835 560.2629 1089

1.99 559.2835 560.2698 1090

2.02 628.3447 629.3398 1091

2 593.2348 594.2117 1092

1.95 559.2835 560.2643 1093

2.02 593.2445 594.2274 1094

2.03 573.2991 574.271 1095

1.71 607.2617 608.2644 1096

2.11 629.3254 630.3112 1097

2.11 595.341 596.3187 1098

1.89 545.2678 546.2605 1099

1.96 579.2289 580.2228 1100

1.97 559.2835 560.2682 1101

1.94 573.2628 574.2623 1102

1.83 558.3029 559.2951 1103

1.87 531.2886 532.2817 1104

1.93 565.2496 566.248 1105

1.95 565.3042 546.2853 1106

1.89 545.3042 546.2955 1107

1.98 551.3512 552.3348 1108

1.83 594.2301 595.2273 1109

2.01 531.2653 532.2531 1110

1.8 497.3042 498.2937 1111

1.96 525.2991 526.2787 1112

2.04 565.2496 566.2412 1113

2.06 559.2835 560.2628 1114

1.89 594.2665 295.256 1115

1.97 252.2991 526.292 1116

1.87 260.2821 561.2739 1117

1.86 560.2821 561.2766 1118

1.88 560.2821 561.2753 1119

1.89 524.3151 525.3075 1120

2 645.2839 646.274 1121

1.99 651.25 652.2567 1122

2.01 631.3049 632.2967 1123

1.89 644.3362 645.35 1124

2.01 631.2682 632.2625 1125

2 637.2344 638.2382 1126

2.01 617.289 618.2725 1127

1.9 630.3206 631.3359 1128

2.07 627.2709 628.2573 1129

2.02 573.2991 574.2791 1130

1.92 586.3307 587.3427 1131

1132

1.87 561.2991 562.3006 1133

1134

1135

1136

1137

1138

1139

1140

1.81 558.3359 559.3449 1141

1.96 603.2369 604.2373 1142

1.95 609.2031 610.2124 1143

2.02 613.2552 614.2456 1144

1.96 559.2835 560.2794 1145

1.86 572.3151 573.3293 1146

1.98 603.2733 604.278 1147

2.05 575.3148 576.3073 1148

2.04 539.3148 540.3035 1149

2.01 631.3046 632.2966 1150

1.91 508.3202 509.323 1151

2.1 535.3563 536.3535 1152

2.07 521.3406 522.3412 1153

1.88 511.3199 512.3171 1154

1.85 575.3148 576.3098 1155

1.91 509.3406 510.3491 1156

1.86 495.325 496.3272

TABLE 2A

H+ CMP R4 is H unless otherwise specified Rtn. Cmp. Ion # R1 R2 R3 R4 R5R6 Time Mass Obs 1157

1.98 451.2987 452.3944 1158

2.07 485.2831 486.3753 1159

2.05 515.2936 516.3962 1160

2.15 491.33 492.4342 1161

2.11 529.2093 530.32 1162

2.11 563.1936 564.31 1163

2.11 593.2042 594.33 1164

1165

2.05 469.2893 470.3595 1166

2.06 503.2737 504.3713 1167

2.05 533.2442 534.3885 1168

2.15 504.3206 510.9258 1169

2.10 485.2578 486.3618 1170

2.09 579.2441 520.3508 1171

2.10 549.2547 550.3768 1172

2.18 525.2911 526.4115 1173

2.06 465.3144 466.4148 1174

2.10 499.2987 500.4062 1175

2.10 529.3093 530.4219 1176

1177

1.86 481.3093 482.4177 1178

2.07 515.2036 516.4023 1179

2.06 545.3042 546.4252 1180

2.12 621.3408 622.4584 1181

2.11 619.2881 520.4012 1182

2.09 553.2705 554.3881 1183

2.1 583.2811 584.4048 1184

2.17 559.3174 560.4424 1185

1.95 495.325 496.4399 1186

2.11 529.3093 530.4105 1187

2.09 559.3199 560.4452 1188

1189

2.15 519.2208 520.3397 1190

2.15 553.2051 554.3284 1191

2.26 559.2521 560.3608 1192

1.85 511.3199 512.4327 1193

2.05 545.3042 546.4219 1194

2.04 575.3148 576.4352 1195

2.09 551.3512 552.4758 1196

1.91 511.3199 512.4281 1197

2.05 545.3042 546.4178 1198

2.05 575.3148 576.4329 1199

2.12 551.3512 552.4684 1200

2.09 529.2093 530.33 1201

2.11 563.1936 564.32 1202

2.11 593.2042 594.34 1203

1204

2 469.2893 470.3277 1205

2.05 503.2737 504.3181 1206

2.14 509.3206 510.3687 1207

2.06 485.2598 486.3074 1208

2.1 519.2441 520.2955 1209

2.09 549.2547 550.3127 1210

2.19 525.2911 526.3676 1211

1.99 465.3144 466.3585 1212

2.1 499.2987 500.3643 1213

1214

2.19 505.3457 506.4082 1215

2.04 479.33 480.3875 1216

2.13 513.3144 514.3647 1217

2.13 543.325 544.3829 1218

2.22 519.3813 520.4385 1219

1.91 481.3093 482.3635 1220

2.06 515.2936 516.3668 1221

2.05 545.3042 546.3696 1222

2.13 521.3406 522.4055 1223

1.97 495.325 496.3876 1224

2.09 529.3093 530.3716 1225

2.08 559.3199 560.3892 1226

2.17 535.3563 536.4433 1227

2.06 523.3563 524.4395 1228

2.17 557.3406 558.4227 1229

2.16 587.3512 588.4426 1230

2.26 563.3876 564.4906 1231

2.08 519.2861 520.3691 1232

2.09 553.2705 554.355 1233

2.08 583.2811 584.3691 1234

2.17 559.3174 560.4126 1235

2.07 493.3457 494.4268 1236

2.17 527.3301 528.4103 1237

2.15 557.3406 558.4276 1238

1239

2.11 527.3301 528.4191 1240

2.16 561.3144 562.409 1241

2.15 591.325 592.4272 1242

2.26 567.3613 568.463 1243

1.94 495.2886 496.3611 1244

2.05 529.2729 530.3501 1245

2.04 559.2835 560.3697 1246

2.13 535.3199 536.4042 1247

1.94 509.3042 510.3796 1248

2.05 543.2886 544.3738 1249

2.04 573.2991 574.3901 1250

2.13 549.3355 550.4245 1251

2.1 543.325 544.4181 1252

2.24 583.3563 584.4531 1253

1.82 541.3304 542.4101 1254

2.02 575.3148 576.4094 1255

1.97 605.3254 606.4261 1256

2 581.3618 582.4799 1257

2.25 597.3719 598.4869 1258

2.04 557.3406 558.4506 1259

2.15 621.3355 622.458 1260

2.24 597.3719 598.4882 1261

2.02 587.3512 588.4437 1262

2.09 621.3355 622.4498 1263

2.16 627.3825 628.4863 1264

2.18 627.3825 628.485 1265

1266

1267

1268

1269

1.91 511.3199 512.4009 1270

2.04 545.3042 546.3881 1271

2.03 575.3148 576.4091 1272

2.12 551.3512 552.4484 1273

1.85 511.3199 512.394 1274

1.99 545.3042 546.3782 1275

1.97 575.3148 576.4008 1276

2.07 551.3512 552.4422 1277

2.02 560.2787 561.3565 1278

2 526.2944 527.3669 1279

2.08 556.3257 567.418 1280

2.05 530.2449 531.3361 1281

2.05 594.2397 595.334 1282

2.12 570.2762 571.3751 1283

2.07 594.2397 595.3354 1284

2.08 479.33 480.4123 1285

2.14 513.3144 514.3954 1286

2.13 543.325 544.4046 1287

1288

2.05 487.2799 488.3539 1289

2.06 521.2643 522.3414 1290

2.05 551.2748 552.3583 1291

2.14 527.3112 528.4017 1292

2.14 519.2208 520.312 1293

2.13 583.2157 584.3151 1294

1295

1296

2.14 651.2684 652.3798 1297

1298

2.06 487.2799 488.3528 1299

2.05 521.2643 522.3441 1300

2.06 551.2748 552.3575 1301

2.14 527.3112 528.3984 1302

2.14 519.2208 520.3089 1303

2.13 583.2157 584.3103 1304

1305

2.14 519.2208 520.3032 1306

2.13 553.2051 554.2903 1307

2.13 583.2157 584.3069 1308

1309

2.11 503.2504 504.3281 1310

2.09 537.2347 538.3116 1311

2.09 567.2452 568.3282 1312

2.18 543.2817 544.3722 1313

2.08 487.2799 488.381 1314

2.05 521.2643 522.3368 1315

2.06 551.2748 552.3557 1316

2.16 527.3112 528.3931 1317

2.07 487.2799 288.3499 1318

2.05 521.2643 522.3353 1319

2.06 551.2748 552.3566 1320

2.14 527.3112 528.3936 1321

2.08 487.2799 488.3528 1322

2.08 521.2643 522.3411 1323

2.06 551.2748 552.3599 1324

2.17 527.3112 528.3907 1325

2.13 535.2811 336.38 1326

2.12 569.2654 570.3573 1327

2.11 599.2759 600.3768 1328

2.19 575.3124 576.4055 1329

2.01 517.2905 518.3644 1330

2.05 551.2748 552.3568 1331

2.04 581.2854 582.3729 1332

2.12 557.3218 558.4104 1333

2.1 535.2811 536.3671 1334

2.11 569.2654 570.3599 1335

2.11 599.2759 600.3785 1336

2.18 575.3124 576.4045 1337

2.08 487.2799 488.3532 1338

2.08 521.2643 522.3442 1339

2.07 551.2748 552.3596 1340

2.16 527.3112 528.3984 1341

2.1 503.2504 504.3321 1342

2.1 537.2347 538.3232 1343

2.1 567.2452 568.3386 1344

1345

2.09 537.2767 538.3624 1346

2.09 571.261 572.3517 1347

2.08 601.2716 602.369 1348

2.16 577.308 578.4044 1349

2.1 547.1998 548.2905 1350

2.11 581.1842 582.29 1351

2.1 611.1948 612.3 1352

2.19 587.2311 598.34 1353

2.05 559.2198 560.31 1354

1355

2.08 623.2147 624.31 1356

1357

2.02 509.3406 510.4212 1358

2.14 543.325 544.3982 1359

2.13 573.3355 574.4336 1360

1361

2.11 507.3614 508.4463 1362

2.19 541.3457 542.4313 1363

2.18 571.3563 572.447 1364

1365

1.98 499.2999 500.366 1366

2.05 533.2842 534.366 1367

2.04 563.2948 564.3766 1368

1369

1.87 423.2675 424.3263 1370

1.93 437.2831 438.3482 1371

1.97 451.2987 452.3679 1372

2.03 501.1779 502.2567 1373

2.08 515.1936 516.27 1374

2.12 529.2093 530.29 1375

1.96 441.528 442.3157 1376

2.01 455.2737 456.3356 1377

2.05 469.2893 470.3576 1378

2.02 457.2285 458.3003 1379

2.07 471.2441 472.3165 1380

2.11 485.2598 486.3203 1381

1.97 437.2831 438.3451 1382

2.02 451.2987 452.3678 1383

1.85 467.2937 468.3646 1384

1.88 481.3093 482.3853 1385

2.04 491.2548 492.3256 1386

2.07 505.2705 506.3494 1387

2.11 519.2861 520.37 1388

1.84 467.2937 468.3647 1389

1.91 481.3093 482.3842 1390

1.96 495.325 496.4054 1391

2.13 505.2051 506.2906 1392

2.16 519.2208 520.3135 1393

1.81 497.3042 498.3747 1394

1.86 511.3199 512.4008 1395

1.8 483.2886 484.2823 1396

1.86 497.3042 498.2973 1397

1.91 511.3199 512.3188 1398

2.01 501.1779 502.1894 1399

2.06 515.1936 516.206 1400

2.08 529.2093 530.222 1401

1.94 441.258 442.2664 1402

2 455.2737 456.28 1403

2.03 469.2893 470.2926 1404

1.9 437.2831 438.2925 1405

1.96 451.2987 452.3093 1406

2 465.3144 466.3223 1407

2 491.2548 492.2683 1408

2.05 505.2705 506.2844 1409

2.08 519.2861 520.2956 1410

1411

1.95 467.2937 467.1446 1412

1.98 481.3093 482.2171 1413

2 457.2285 458.1478 1414

2.04 471.2441 472.1711 1415

2.09 485.2598 486.1973 1416

2.05 515.2936 516.2304 1417

2.09 529.3093 530.2516 1418

2.12 543.325 544.2772 1419

2 503.2384 504.2027 1420

2.06 517.2541 518.2202 1421

2.08 531.2697 532.2498 1422

X₆—CH₃ 1.96 487.1623 488.1573 1423

1.98 501.1779 502.1747 1424

2.04 515.1936 516.1976 1425

2.09 529.2093 530.21 1426

1.89 441.258 442.2531 1427

1.95 455.2737 456.2708 1428

2 469.2893 470.2896 1429

1.96 457.2285 458.2379 1430

2.03 471.2441 472.2611 1431

2.06 485.2598 486.2763 1432

1.89 437.2831 438.2931 1433

1.94 451.2987 452.3127 1434

1.98 465.3144 466.3366 1435

X₆—C₃ 1.9 437.2831 438.2971 1436

1.93 451.2987 452.3194 1437

1.99 485.3144 466.3413 1438

2.03 479.33 480.3666 1439

1.81 453.278 454.3067 1440

1.88 467.2937 468.3209 1441

1.91 481.3093 482.3407 1442

1.87 467.2937 468.3278 1443

1.93 481.3093 482.3481 1444

1.95 495.325 496.3688 1445

X₆—CH₃ 1.95 481.3093 482.356 1446

1.97 495.325 496.3746 1447

2.03 509.3406 510.4019 1448

2.05 523.3563 514.4143 1449

2.05 505.2705 506.3199 1450

2.08 519.2861 520.3441 1451

X₆—CH₃ 1.95 451.2987 452.3453 1452

1.97 465.3144 466.3662 1453

2.03 479.33 480.3838 1454

2.07 493.3457 494.4073 1455

2.07 513.3144 514.367 1456

X₆—CH₃ 1.8 453.2416 454.2823 1457

1.83 467.2573 468.2991 1458

1.9 481.2729 482.3186 1459

1.94 495.2886 496.3361 1460

1.82 481.2729 482.3166 1461

1.89 495.2886 496.3342 1462

1.93 509.3042 510.3551 1463

2 515.2936 516.3452 1464

2.07 529.3093 530.368 1465

2.08 543.325 544.3928 1466

1.96 529.3093 530.3663 1467

2.02 543.325 544.387 1468

2.05 557.3406 558.4091 1469

1.97 573.3355 574.3986 1470

2.01 687.3612 688.4052 1471

2 587.3512 588.4127 1472

1473

1474

1.87 497.3042 498.347 1475

1.91 511.3199 512.3705 1476

1.85 511.3199 512.367 1477

1.93 437.2831 438.3286 1478

2.01 465.3144 466.3688 1479

2.09 515.1936 516.2552 1480

2.14 543.2249 544.29 1481

2 455.2737 456.3135 1482

2.08 483.305 484.3603 1483

2.04 457.2285 458.2748 1484

2.06 471.2441 472.2965 1485

2.13 499.2754 500.3322 1486

2.1 479.33 480.3871 1487

1.84 467.2937 468.3388 1488

1.93 495.325 496.3778 1489

2.07 505.2705 506.284 1490

1.91 481.3093 482.3268 1491

2 509.3406 510.3873 1492

1.81 497.3042 498.338 1493

1.89 525.3355 526.3815 1494

1.86 497.3042 498.333 1495

1.94 525.3355 526.3823 1496

2 455.2737 456.3067 1497

1.95 451.2987 452.3412 1498

2.05 479.33 480.3812 1499

1.95 467.2937 468.3324 1500

2.02 495.325 496.3728 1501

2.06 471.2441 472.2934 1502

2.05 516.1936 516.24 1503

2.12 543.2249 544.28 1504

1.95 455.2737 456.315 1505

2.04 283.305 484.3472 1506

2.04 471.2441 472.2987 1507

2.1 499.2754 500.3232 1508

1.93 437.2831 438.3264 1509

1.94 451.2987 452.3422 1510

2.03 479.33 480.3817 1511

1.94 437.2831 438.3318 1512

1.98 451.2987 452.3448 1513

2 465.3144 466.3637 1514

1515

1.87 467.2937 468.338 1516

1.96 495.325 496.3754 1517

1.9 467.2937 468.3403 1518

1.92 481.3093 482.358 1519

2 509.3406 510.3971 1520

2.03 509.3406 510.3994 1521

1522

2.12 533.3018 534.3584 1523

2.01 465.3144 466.3678 1524

2.04 479.33 480.3809 1525

1526

1.88 467.2573 468.2988 1527

1.91 481.2720 482.3167 1528

1.99 509.3042 510.3497 1529

1.88 481.2729 482.3152 1530

1.89 495.2666 496.3308 1531

1.97 523.3199 524.3652 1532

1533

1534

2.04 601.3668 602.4158 1535

1.9 525.3355 526.3354 1536

2.1 485.2598 486.306 1537

1.8 483.2886 484.3271 1538

1.86 497.3042 498.3447 1539

1.91 511.3199 512.3699 1540

2.02 501.1779 502.23 1541

2.07 515.1936 516.24 1542

2.11 529.2093 530.27 1543

1.94 441.258 442.2997 1544

1.99 455.2737 456.321 1545

2.04 469.2893 470.3382 1546

1.97 461.2987 462.3466 1547

2 465.3144 466.3688 1548

2.01 491.2548 492.3076 1549

2.06 505.2705 506.3239 1550

2.09 610.2881 620.3437 1551

1.88 453.278 454.32 1552

1.95 487.2937 466.3404 1553

1.98 481.3093 482.3591 1554

1.99 457.2285 458.2789 1555

2.05 471.2441 472.2944 1556

2.09 485.2598 486.3078 1557

2.11 529.3093 530.3656 1558

2.05 515.1936 516.25 1559

2.09 529.2093 630.2776 1560

1.97 455.2737 456.3232 1561

2 469.2893 470.3403 1562

1.98 457.2285 458.2803 1563

2.03 471.2441 472.2929 1564

2.07 485.2598 486.3048 1565

1.95 451.2987 452.3497 1566

1.99 465.3144 466.3694 1567

1.94 451.2987 452.3482 1568

2 465.3144 466.3705 1569

2.04 479.33 480.3848 1570

1.81 453.278 454.3195 1571

1.88 467.2937 468.3429 1572

1.92 481.3093 482.358 1573

1.87 467.2937 468.3413 1574

1.92 481.3093 182.3646 1575

1.96 495.326 496.383 1576

2.03 509.3406 510.391 1577

1578

2.05 505.2705 506.3306 1579

2.09 519.2861 520.3426 1580

1.98 465.3144 466.3676 1581

1582

1583

2.07 513.3144 514.3667 1584

2.07 526.258 527.32 1585

2.06 554.2893 555.3538 1586

2.03 451.2987 452.3538 1587

2.05 465.3144 466.3634 1588

2.12 493.3457 494.4006 1589

2.03 473.2643 474.2992 1590

2.1 501.2956 502.3373 1591

2.1 491.1895 192.2394 1592

2.11 505.2051 506.2584 1593

2.18 533.2365 534.3019 1594

2.06 475.2191 476.2581 1595

2.08 489.2347 490.2856 1596

2.14 517.266 518.3196 1597

2.04 473.2643 474.3057 1598

2.1 501.2956 502.3344 1599

2 445.2329 446.2716 1600

2.02 459.2486 460.2865 1601

2.05 473.2643 474.3071 1602

2.1 501.2956 502.3315 1603

1.98 445.2329 446.2758 1604

2.03 473.2643 474.3029 1605

2.1 501.2956 502.3305 1606

2.03 485.2842 486.3231 1607

2.09 513.3156 514.3523 1608

1.85 527.3148 528.3573 1609

1.93 555.3461 556.3929 1610

2.06 509.3042 510.3471 1611

1.9 467.2937 467.3423 1612

1.92 481.3093 482.3568 1613

2 509.3406 510.4003 1614

1.89 511.3199 512.3646 1615

1.96 539.3512 540.4082 1616

2.05 491.2548 492.3016 1617

2.07 523.261 524.3156 1618

1.99 481.3093 482.3597 1619

2 495.325 496.3752 1620

2.07 523.3563 524.4204 1621

2.02 531.2653 532.3195 1622

2.09 559.2966 560.3568 1623

2.09 489.2347 490.2897 1624

2.14 517.266 518.3209 1625

1.87 525.3355 526.3839 1626

1.86 511.3199 512.3685 1627

1.83 497.3042 498.3462 1628

1.91 525.3355 526.3853 1629

1.85 511.3199 512.3719 1630

1.96 561.1991 562.2613 1631

2.03 589.2304 590.29 1632

1.88 467.2937 468.3345 1633

1.97 495.325 496.3788 1634

1.77 453.278 454.3158 1635

1.81 467.2937 468.3368 1636

1.81 497.3042 498.3435 1637

1.89 525.3355 526.3845 1638

1.77 453.278 454.3218 1639

1.8 467.2937 468.3422 1640

1.82 481.3093 482.3608 1641

1642

1.73 439.2624 440.3095 1643

1.77 453.278 454.3231 1644

1.81 467.2937 468.3407 1645

1.88 495.325 496.385 1646

2.11 563.1703 564.29 1647

1648

2.06 499.2999 500.3384 1649

1650

2.16 553.1818 554.31 1651

1652

2.01 495.325 496.3744 1653

1654

2 499.2999 500.344 1655

1656

2 511.3199 512.3674 1657

1658

1659

1660

1661

1.99 495.325 496.3893 1662

1663

2.04 509.3406 510.4029 1664

1665

1.92 511.3199 512.3715 1666

1667

1.96 525.3355 526.388 1668

1669

2.06 553.3668 554.4324 1670

1671

1672

2.08 523.3563 524.4255 1673

1674

1.98 513.2792 514.3397 1675

1676

1.95 525.2991 526.3698 1677

1678

1.97 527.2948 528.3601 1679

1680

1.95 539.3148 540.3774 1681

1682

1683

1684

1685

1686

1.91 541.3304 542.3954 1687

1.89 529.3105 530.3705 1688

1689

1690

1691

2.03 556.3049 557.3685 1692

1693

1694

1695

2.15 553.1818 554.32 1696

1697

2.15 553.1818 554.31 1698

1699

2.09 505.2705 506.3293 1700

1701

1702

1703

1.97 609.1758 608.2943 1704

1.95 499.2999 500.3528 1705

1706

1707

1708

1.87 529.3105 530.3679 1709

1710

1.89 513.3156 514.3675 1711

1712

1.86 525.3355 526.3887 1713

1714

1.88 499.2999 500.3582 1715

1716

1.83 511.3199 512.3775 1717

1718

1719

1.91 485.2842 486.3395 1720

1721

1.89 497.3042 498.3563 1722

1723

1.86 515.2948 516.3523 1724

1725

1.83 486.2842 486.3419 1726

1.8 497.3042 498.3629 1727

1728

1.83 515.2948 516.3555 1729

1730

2.04 519.2452 520.3127 1731

1732

1733

1.88 571.341 572.4042 1734

1735

1736

1.96 525.3355 526.3864 1737

1.96 543.3261 544.3817 1738

1739

1.92 555.3461 556.3982 1740

1741

1742

1743

1744

1745

2.02 535.2811 536.3478 1746

1747

1748

1749

1750

1751

1752

1753

2.07 589.2304 590.3111 1754

2.04 527.3312 528.3896 1755

1756

2.02 539.3512 540.4099 1757

1758

2.1 537.3719 538.4346 1759

TABLE 3

CMP # R1 R2 R3 R4 R5 Rtn. Time Cmp. Mass H + Ion Obs 1800

1.9 531.2158 532.2805 1801

1802

1.98 565.2132 566.2751 1803

1.99 515.2573 516.3182 1804

1.96 559.2471 560.3251 1805

1.87 481.2729 482.34 1806

2.01 521.2234 522.2883 1807

1.91 487.239 488.3032 1808

2.07 515.2573 516.2889

TABLE 4

CMP Rtn. Cmp. H + # R1 R2 R3 and R4 R5 R6 Time Mass Ion Obs 1809

2.04 493.2729 494.3307 1810

2.02 499.239 500.3034 1811

1812

1813

1814

2.01 485.2234 486.3 1815

1816

1817

2.05 521.3042 522.3529 1818

2.08 493.286 494.3401 1819

2.02 459.325 460.3719 1820

2.01 469.325 460.3708 1821

2.05 527.2703 628.3184 1822

2.04 501.3355 502.3303 1823

1.99 487.3199 488.3148

TABLE 5

Rtn. Cmp. H + CMP # R1 R2 R3 Time Mass Ion Obs 1832

2 447.231 448.2516 1833

1.91 444.2413 445.2811 1834

1835

2.36 433.2042 434.2552 1836

2.33 433.2042 434.2509 1837

2.33 433.2042 434.2613 1838

2.22 419.1885 420.2401 1839

2.3 505.2253 506.2785 1840

2.31 421.2042 422.2463 1841

2.2 419.1885 420.2424 1842

2.27 419.1885 420.2401 1843

2.32 505.2253 506.2746 1844

2.3 505.2253 506.2814 1845

2.27 421.1678 422.2155 1846

2.4 427.1936 428.2449 1847

2.33 413.1991 414.2406 1848

2.25 465.1576 466.216 1849

2.12 420.2202 421.262 1850

2.33 489.1552 490.2146 1851

2.46 495.181 496.2438 1852

2.37 481.1865 482.2455 1853

2.17 488.2076 489.2776 1854

2.4 471.181 472.2344 1855

2.49 457.2042 458.2641 1856

2.4 443.2097 444.2538 1857

2.42 433.2042 434.2522 1858

1859

1860

1861

2.17 490.2369 491.2785 1862

2.1 479.2321 480.2817 1863

1864

1865

1866

2.15 485.2027 486.248 1867

2.29 472.1762 473.2223 1868

1.78 411.1583 412.1952 1869

2.44 443.1111 444.1614 1870

2.4 423.1657 424.1971 1871

2.11 504.2577 505.2372 1872

2.08 508.2326 509.2144 1873

2.21 524.2031 525.1942 1874

2.4 558.2294 559.21 1875

2.01 490.242 491.2217 1876

2.11 524.2031 525.1987 1877

2.04 508.2326 509.2227 1878

2.43 417.2093 418.29 1879

2.42 417.2093 418.2941 1880

2.4 417.2093 418.2959 1881

2.35 421.1842 422.275 1882

2.53 411.2562 412.3455 1883

2.57 423.2562 424.3539 1884

2.42 437.1546 438.1642 1885

2.37 417.2093 418.2095 1886

2.41 417.2093 418.2095 1887

2.42 431.2249 432.2221 1888

2.48 517.0903 518.1107 1889

2.46 429.2093 430.2187 1890

2.48 429.2093 430.2192 1891

2.41 433.1842 434.2012 1892

2.46 469.1041 470.13 1893

2.21 549.1182 550.13 1894

2.49 393.2126 394.2145 1895

2.39 407.246 408.2388 1896

2.75 477.1837 478.2005 1897

1898

2.6 525.1529 526.1517 1899

2.47 409.2406 410.246 1900

2.58 437.2719 438.2745 1901

2.38 433.2042 434.2162 1902

2.44 413.2355 414.2371 1903

2.42 413.2355 414.239 1904

2.39 413.2355 414.2406 1905

2.27 401.1991 402.2075 1906

2.28 401.1991 402.2055 1907

2.3 421.1445 422.163 1908

2.28 411.1446 412.1578 1909

2.47 407.246 408.2634 1910

2.45 407.246 408.2503 1911

2.46 415.2123 416.2284 1912

2.16 508.2281 509.2342 1913

1.99 524.2231 525.2272 1914

2.19 528.1735 529.1874 1915

2.38 562.1999 563.214 1916

1917

1918

2.13 494.2482 495.2661 1919

1920

2.13 449.2216 450.2522 1921

2.11 467.2121 468.2447 1922

2.14 467.2121 468.2424 1923

2.11 479.2321 480.2583 1924

2.52 400.2515 401.2748 1925

2.52 412.2515 413.2805 1926

2.28 346.2045 347.2321 1927

2.25 366.1732 367.2062 1928

2.11 531.3097 532.3127 1929

1.96 503.2243 504.2599 1930

2 517.2399 518.2693 1931

1.96 519.2534 520.2534 1932

2.02 505.2132 506.2226 1933

2.05 529.2941 530.2949 1934

2.03 529.2941 530.2936 1935

1.92 531.2733 532.2859 1936

1.91 531.2733 532.2828 1937

2.27 520.203 521.2229 1938

2.25 520.203 521.2301 1939

2.32 534.2186 535.2426 1940

2.19 540.1695 541.1906 1941

2.23 560.0978 561.14 1942

2.23 560.0978 561.14 1943

2.28 574.1135 575.16 1944

1945

2.19 497.1982 498.2381 1946

2.26 511.2139 512.2437 1947

2.25 511.2139 512.2531 1948

2.3 520.203 521.2333 1949

2.25 497.1982 498.2341 1950

2.25 497.1982 498.2305 1951

2.3 511.2139 512.2459 1952

2.3 511.2139 512.2452 1953

2.07 504.2577 505.2828 1954

2.07 504.2577 505.2755 1955

2.05 508.2326 509.2624 1956

2.03 520.2526 521.2831 1957

1958

2.05 486.2671 487.2196 1959

2.06 486.2671 487.2379 1960

2.02 502.262 503.2366 1961

2.55 507.098 508.09 1962

2.49 449.1329 450.125 1963

2.49 449.1329 450.1363 1964

2.55 463.1485 464.155 1965

2.5 461.1329 462.152 1966

2.13 508.115 509.1421 1967

2.39 437.1546 438.191 1968

2.1 520.1011 521.1198 1969

2.16 486.2307 487.2447 1970

2.01 424.2151 425.2368 1971

2.08 472.115 473.1456 1972

2.38 437.1546 438.1952 1973

2.37 431.2249 432.2486 1974

2.38 437.1546 438.1897 1975

2.33 403.1936 404.224 1976

2.36 415.1936 416.2279 1977

2.3 421.1842 422.218 1978

2.29 433.2042 434.2361 1979

2.32 447.2198 448.251 1980

1.88 547.2026 548.3105 1981

1.9 549.2228 550.3254 1982

1.97 525.2592 526.3528 1983

1.94 577.2132 578.3243 1984

2.01 553.2496 554.3531 1985

1.92 581.229 582.3329 1986

1.95 551.1531 552.2697 1987

1.95 581.1637 582.2848 1988

2.03 557.2001 558.311 1989

1.9 591.1522 592.27 1990

2.02 617.3042 618.4236 1991

1.92 639.1383 640.2621 1992

1.95 607.2238 608.3556 1993

1.92 621.1627 622.29 1994

1.96 651.1733 652.31 1995

1.93 657.1288 658.2678 1996

1.95 605.1678 606.29 1997

2.02 581.2042 582.32 1998

1.96 593.1904 594.3127 1999

1.97 615.1901 616.3185 2000

2.04 591.2264 592.3466 2001

1.93 578.2682 579.3848 2002

2003

2004

2005

2006

2.47 475.2511 476.2856 2007

2.36 403.1936 404.2317 2008

2.42 427.1936 428.2387 2009

2.43 437.1546 438.2044 2010

2.39 433.15 434.1996 2011

2.39 445.1842 446.226 2012

2.41 455.1452 456.196 2013

2.41 433.15 434.1984 2014

2.42 443.1111 444.1632 2015

2.47 443.1111 444.1649 2016

2.53 477.0721 478.137 2017

2.41 423.1657 424.2055

TABLE 6

R1 or Rtn. Cmp H+ CMP # R1 and R2 R3 R4 R5 R6 time Mass Ion Obs 1824

1.91 424.2151 425.2364 1825

2.17 558.2518 559.2742 1826

2.2 514.262 515.286 1827

2.09 508.2362 509.2629 1828

2.1 464.2464 465.2729 1829

2.04 514.2023 515.2661 1830

1.98 436.2281 437.2896 1831

2.06 470.2126 471.2746

1. A compound of the formula:

or a pharmaceutically acceptable salt, prodrug or hydrate thereof,wherein: n is an integer from 0 to 3; R₂ is chosen from optionallysubstituted C₁–C₈ alkyl, optionally substituted C₃–C₈ cycloalkyl,optionally substituted C₃–C₈ cycloalkyl(C₁–C₈)alkyl optionallysubstituted C₂–C₈ alkenyl, optionally substituted C₂–C₈ alkynyl,haloalkyl, and aminoalkyl, each of which is unsubstituted or substitutedwith one or more substituents selected from oxo, hydroxy, alkoxy, amide,ester, cyano, acetoxy and nitro; R₄ is hydrogen or alkyl, alkenyl,alkynyl, cycloalkyl, (cycloalkyl)alkyl or haloalkyl, each of which issubstituted or unsubstituted; or R₄ is optionally substitutedcarbocyclic aryl, optionally substituted arylalkyl, or an optionallysubstituted heteroaromatic or heteroalicyclic group having from 1 to 3rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; R₃ andR_(3A) are the same or different and represent hydrogen or alkyl; or R₃and R_(3A), taken together with the carbon atom to which they areattached, form a cycloalkyl ring; R₅ and R₆ are the same or differentand represent hydrogen, halogen, hydroxy, alkyl, or alkoxy; or R₅ andR₆, taken together with the carbon atom to which they are attached forma cycloalkyl ring; R_(5a) and R_(6a) are independently selected at eachoccurrence from hydrogen, halogen, hydroxy, alkyl, and alkoxy; R₇represents hydrogen or alkyl; Ar₁ is optionally substituted carbocyclicaryl, optionally substituted arylalkyl, or an optionally substitutedheteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8members in each ring and from 1 to 3 heteroatoms; and Ar₂ is optionallysubstituted carbocyclic aryl, optionally substituted arylalkyl, or anoptionally substituted heteroaryl or heteroalicyclic group having from 1to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms. 2.A compound or salt, prodrug or hydrate thereof according to claim 1,wherein: R₄ is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, haloalkyl, each of which is unsubstituted orsubstituted with one or more substituents independently selected fromhalogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino and mono- ordialkylamino, R₄ is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl,phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl,imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl,naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl,benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl,benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl,or quinoxalinyl, each of which is optionally substituted with up to fourgroups independently selected from halogen, nitro, cyano,trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl,alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino, aminoalkoxy,carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono ordialkylaminocarbonyl, N-alkylsulfonylaminocarbonyl, 1-azetidinyl,1-pyrrolidinyl, 1-piperidyl and —X₄R_(B), wherein X₄ and R_(B) are asdefined below; or R₄ is a bicyclic oxygen-containing group of theformula:

wherein R_(A) represents from 0 to 3 groups independently selected fromhalogen, intro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- ordialkylamino; Ar₁ is chosen from i) ethylenedioxyphenyl,methylenedioxyphenyl, phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl,thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl, each of whichis optionally substituted with up to four groups independently selectedfrom halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino,mono- or di-alkylamino, aminoalkoxy, carboxylic acid, esters ofcarboxylic acids, aminocarbonyl, mono- or di-alkylaminocarbonyl,N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyland —X₄R_(B), wherein X₄ and R_(B) are as defined below; and ii)bicyclic oxygen-containing groups of the formula:

 wherein R_(B) represents from 0 to 3 groups independently selected fromhalogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- ordialkylamino; Ar₂ is chosen from i) phenyl, phenylalkyl, chromanyl,pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl,pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl,indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl,benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl,quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl,each of which optionally substituted with up to four groupsindependently selected from halogen, nitro, cyano, trifluoromethyl,trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl,alkoxy, amino, mono- or dialkylamino, aminoalkoxy, carboxylic acid,esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl,N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyland —X₄R_(B), wherein X₄ and R_(B) are as defined below; and ii)bicyclic oxygen-containing groups of the formula:

 wherein R_(B) represents from 0 to 3 groups independently selected fromhalogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- ordialkylamino, X₄ is independently selected at each occurrence from—CH₂—, —CHR_(C)—, —O—, —S(O)_(m)—, —NH—, —NR_(C)—, —C(═O)NH—,—C(═O)NR_(C)—, —S(O)_(m)NH—, —S(O)_(m)NR_(C)—, —NHC(O)—, —NR_(C)C(═O)—,—NHS(O)_(m)—, —C(O)NHS(O)_(m-), and —NR_(C)S(O)_(m)wherein m is 0, 1, or2; and R_(B) and R_(C) are independently selected at each occurrencefrom: hydrogen and straight, branched, or cyclic alkyl groups, whichoptionally contain one or more double or triple bonds, each of which isunsubstituted or substituted with one or more substituent(s)independently selected from: oxo, hydroxy, —O(alkyl), —NH(alkyl),—N(alkyl)(alkyl), —NHC(O)(alkyl), —N(alkyl)C(O)(alkyl),—NHS(O)_(x)(alkyl), —S(O)_(x)(alkyl), —S(O)_(x)NH(alkyl), and—S(O)_(x)N(C₁–C₆ alkyl)(C₁–C₆ alkyl), (wherein x is 0, 1, or
 2. 3. Acompound or salt, prodrug or hydrate thereof according to claim 1,wherein: R₃ and R_(3A) are the same or different and represent hydrogenor C₁–C₆ alkyl; or R₃ and R_(3A), taken together with the carbon atom towhich they are attached, form a C₃₋₈ cycloalkyl ring; R₅ and R₆ are thesame or different and represent hydrogen, halogen, hydroxy, C₁–C₆ alkyl,or C₁–C₆ alkoxy; or R₅ and R₆, taken together with the carbon atom towhich they are attached form a C₃₋₈ cycloalkyl ring; R_(5a) and R_(6b)are independently selected at each occurrence from hydrogen, halogen,hydroxy, C₁–C₆ alkyl, and C₁–C₆ alkoxy; R₄ is hydrogen or C₁₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈cycloalkyl, (C₃₋₈ cycloalkyl)C₁₋₄alkyl,or haloalkyl, each or which is unsubstituted or substituted with one ormore substituents independently selected from halogen, nitro, cyano,trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino and mono- ordi(C₁–C₆)alkylamino, or R₄ is phenyl, ethylenedioxyphenyl,methylenedioxyphenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl,thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl,benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of whichis optionally substituted with up to four groups independently selectedfrom halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁–C₆ alkoxy, amino, mono- or di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy,carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono ordi(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and —X₄R_(B), wherein X₄ andR_(B) are as defined below; or R₄ is a bicyclic oxygen-containing groupof the formula:

 wherein R_(A) represents from 0 to 3 groups independently selected fromhalogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy,amino, and mono- or di(C₁–C₆)alkylamino; Ar₁ is chosen from i)ethylenedioxyphenyl, methylenedioxyphenyl, phenyl, phenylalkyl,chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl,pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl,indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl,benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl,quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl,each of which is optionally substituted with up to four groupsindependently selected from halogen, nitro, cyano, trifluoromethyl,trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, amino, mono- or di(C₁–C₆)alkylamino,amino(C₁–C₆)alkoxy, carboxylic acid, esters of carboxylic acids,aminocarbonyl, mono or di(C₁–C₆)alkylaminocarbonyl,N—(C₁–C₆)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,1-piperidyl, and —X₄R_(B), wherein X₄ and R_(B) are as defined below;and ii) bicyclic oxygen-containing groups of the formula:

 wherein R_(B) represents from 0 to 3 groups independently selected fromhalogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy,amino, and mono- or di(C₁–C₆)alkylamino; Ar₂ is chosen from i) phenyl,phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl,imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl,naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl,benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl,benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl,and quinoxalinyl, each of which optionally substituted with up to fourgroups independently selected from halogen, nitro, cyano,trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono- ordi(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters ofcarboxylic acids, aminocarbonyl, mono or di(C₁–C₆)alkylaminocarbonyl,N—(C₁–C₆)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,1-piperidyl, and —X₄R_(B), wherein X₄ and R_(B) are as defined below;and ii) bicyclic oxygen-containing groups of the formula:

 wherein R_(B) represents from 0 to 3 groups independently selected fromhalogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy,amino, and mono- or di(C₁–C₆)alkylamino; X₄ is independently selected ateach occurrence from —CH₂—, —CHR_(C)—, —O—, —S(O)_(m)—, —NH—, —NR_(C)—,—C(═O)NH—, —C(O)NR_(C)—, —S(O)_(m)NH—, —S(O)_(m)NR_(C)—, —NHC(═O)—,—NR_(C)C(═O)—, —NHS(O)_(m)—, —C(═O)NHS(O)_(m)—, and—NR_(C)S(O)_(m)wherein x is 0, 1, or 2; and R_(B) and R_(C), which arethe same or different, are independently selected at each occurrencefrom hydrogen and straight, branched, or cyclic alkyl groups, whichoptionally contain one or more double or triple bonds, each of which isunsubstituted or substituted with one or more substituent(s)independently selected from: oxo, hydroxy, —O(C₁–C₆ alkyl), —NH(C₁–C₆alkyl), —N(C₁–C₆ alkyl)(C₁–C₆ alkyl), —NHC(O)(C₁–C₆ alkyl), —N(C₁–C₆alkyl)C(O)(C₁₋₆ alkyl), —NHS(O)_(x)(C₁–C₆ alkyl), —S(O)_(x)(C₁–C₆alkyl), —S(O)_(x)NH(C₁–C₆ alkyl), and —S(O)_(x)N(C₁–C₆ alkyl)(C₁–C₆alkyl), (wherein x is 0, 1, or
 2. 4. A compound or salt, prodrug orhydrate thereof according to claim 1, wherein R₄ is hydrogen or C₁–C₈alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl, C₃–C₈cycloalkyl, (C₃–C₈cycloalkyl)C₁–C₄alkyl, haloalkyl, each of which is unsubstituted or substitutedwith one or more substituents independently selected from halogen,nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, aminoand mono- or di(C₁–C₆)alkylamino, or R₄ is phenyl, ethylenedioxyphenyl,methylenedioxyphenyl, naphthyl, thienyl, pyridyl, pyrimidyl,dihydrobenzofuranyl, furanyl, benzodioxanyl, or indolyl, each of whichis optionally substituted with up to four groups independently selectedfrom halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,C₁–C₆ alkoxy, amino, mono- or di(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy,carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono ordi(C₁–C₆)alkylaminocarbonyl, N—(C₁–C₆)alkylsulfonylaminocarbonyl,1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and —X₄R_(B), wherein X₄ andR_(B) are as defined below; or R₄ is a bicyclic oxygen-containing groupof the formula:

wherein R_(A) represents from 0 to 3 groups independently selected fromhalogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆alkoxy, amino, and mono- or di(C₁–C₆)alkylamino; Ar₁ is phenyl,ethylenedioxyphenyl, methylenedioxyphenyl, thienyl, pyridyl, pyrimidyl,dihydrobenzofuranyl, furanyl, benzodioxanyl, or indolyl, each of whichis unsubstituted or substituted with up to four substituentsindependently selected from: halogen, nitro, cyano, trifluoromethyl,trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- ordi(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters ofcarboxylic acids, aminocarbonyl, mono or di(C₁–C₆)alkylaminocarbonyl,N—(C₁–C₆)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,1-piperidyl, and —X₄R_(B), wherein X₄ and R_(B) are as defined below;Ar₂ is phenyl, naphthyl, thienyl, pyridyl, pyrimidyl,dihydrobenzofuranyl, furanyl, benzodioxanyl, or indolyl, each of whichis optionally substituted or substituted with up to four groupsindependently selected from halogen, nitro, cyano, trifluoromethyl,trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- ordi(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters ofcarboxylic acids, aminocarbonyl, mono or di(C₁–C₆)alkylaminocarbonyl,N—(C₁–C₆)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,1-piperidyl, and —X₄R_(B), wherein X₄ and R_(B) are as defined below; orAr₂ is a bicyclic oxygen-containing group of the formula:

 wherein R_(A)′ represents from 0 to 3 groups independently selectedfrom halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,C₁–C₆ alkoxy, amino, and mono- or di(C₁–C₆)alkylamino; X₄ isindependently selected at each occurrence from the group consisting of—CH₂—, —CHR_(C)—, —O—, —S(O)_(m)—, —NH—, —NR_(C)—, —C(═O)NH—,—C(O)NR_(C)—, —S(O)_(m)NH—, —S(O)_(m)NR_(C)—, —NHC(═O)—, —NR_(C)C(═O)—,—NHS(O)_(m)—, —C(═O)NHS(O)_(m)—, and —NR_(C)S(O)_(m)— wherein m is 0, 1,or 2; and R_(B) and R_(C), which are the same or different, areindependently selected at each occurrence from: hydrogen and straight,branched, or cyclic alkyl groups, which optionally contain one or moredouble or triple bonds, each of which is unsubstituted or substitutedwith one or more substituent(s) independently selected from: oxo,hydroxy, —O(C₁–C₆ alkyl), —NH(C₁–C₆ alkyl), —N(C₁–C₆ alkyl)(C₁–C₆alkyl), —NHC(O)(C₁–C₆ alkyl), —N(C₁–C₆ alkyl)C(O)(C₁–C₆ alkyl),—NHS(O)_(x)(C₁–C₆ alkyl), —S(O)_(x)(C₁–C₆ alkyl), —S(O)_(x)NH(C₁–C₆alkyl), and —S(O)_(x)(C₁–C₆ alkyl)(C₁–C₆ alkyl), wherein x is 0, 1, or2.
 5. A compound or salt, prodrug or hydrate thereof according to claim4 wherein: R₃ and R₄ are the same or different and represent hydrogen ormethyl; R₅ and R₆ are the same or different arid represent hydrogen ormethyl; and R_(5a) and R_(6a) are independently selected at eachoccurrence from hydrogen and methyl.
 6. A compound or salt, prodrug orhydrate thereof according to claim 4 wherein: R₃ and R₄ are hydrogen; R₅and R₆ are the same or different and represent hydrogen or methyl; andR_(5a) and R_(6a) are independently selected at each occurrence fromhydrogen and methyl.
 7. A compound according to claim 4 of the formula:

or a pharmaceutically acceptable salt, prodrug or hydrate thereof,wherein: R₅ and R₆ are the same or different and represent hydrogen ormethyl; R_(5a) and R_(6a) are independently chosen at each occurrencefrom hydrogen and methyl; and R_(X) represents up to four substituentsindependently chosen from hydrogen, halogen, nitro, cyano,trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, amino, mono- ordi(C₁–C₆)alkylamino, and amino(C₁–C₆)alkoxy.
 8. A compound according toclaim 6, of the formula:

or a pharmaceutically acceptable salt, prodrug or hydrate thereof,wherein: R₂ is C₃–C₈ straight or branched chain alkyl, C₂–C₈ alkenyl, orC₂–C₈ alkynyl; R₅ and R₆ are the same or different and representhydrogen or methyl; R_(5a) and R_(6a) are independently chosen at eachoccurrence from hydrogen and methyl, and R_(X) represents up to foursubstituents independently chosen from hydrogen, halogen, nitro, cyano,trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl, C₁–C₆ alkoxy, amino, mono- ordi(C₁–C₆)alkylamino, and amino(C₁–C₆)alkoxy.
 9. A compound according toclaim 7, or a pharmaceutically acceptable salt, prodrug or hydratethereof, wherein: R₂ is C₃–C₈ straight or branched chain alkyl, C₂–C₈alkenyl, or C₂–C₈ alkynyl; and R₄ is C₁–C₈ straight or branched chainalkyl, C₂–C₈ alkenyl, or C₂–C₈ alkynyl.
 10. A compound according toclaim 7, or a pharmaceutically acceptable salt, prodrug or hydratethereof, wherein: R₂ is C₃–C₈ straight or branched chain alkyl, C₂–C₈alkenyl, or C₂–C₈ alkynyl; R₄ is phenyl, which is unsubstituted orsubstituted with: C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈cycloalkyl, (C₃–C₈ cycloalkyl)C₁–C₄ alkyl, haloalkyl, C₁–C₆ alkoxy,halogen, hydroxy, amino, or mono- or di(C₁–C₆)alkylamino; or R₄ is abicyclic oxygen containing group of the formula:

wherein R_(A) is hydrogen, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,C₃–C₈ cycloalkyl, (C₃–C₈cycloalkyl) C₁–C₄ alkyl, haloalkyl, alkoxy,halogen, hydroxy, amino, or mono- or di(C₁–C₆)alkylamino; Ar₂ is phenylwhich is unsubstituted or substituted with up to four groupsindependently selected from: halogen, C₁–C₇, alkyl, C₁–C₇ alkoxy, cyano,amino, mono- or di(C₁–C₆)alkylamino, carboxylic acid, esters ofcarboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl,N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl,1-morpholino, nitro, hydroxy, acetoxy, trifluoromethyl, trifluoromethoxyand —X₄R_(B), wherein X₄ and R_(B) are as defined for claim 4; or Ar₂ isa bicyclic oxygen-containing group of the formula:

wherein R_(A)′ is as defined in claim
 4. 11. A compound according toclaim 7, or a pharmaceutically acceptable salt, prodrug or hydratethereof, wherein: R₂ is C₃–C₈ straight or branched chain alkyl, C₂–C₈alkenyl, or C₂–C₈ alkynyl; R₄ is C₁–C₈ straight or branched chain alkyl,C₂–C₈ alkenyl, or C₂–C₈ alkynyl; Ar₂ is a bicyclic oxygen containinggroup of the formula:

wherein R_(A)′ is as defined for claim
 4. 12. A process for preparing acompound of the formula:

wherein: n is an integer from 0 to 3; and R₂ is hydrogen or alkyl,alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, or haloalkyl, each ofwhich is substituted or unsubstituted; R₄ is hydrogen or alkyl, alkenyl,alkynyl, cycloalkyl, (cycloalkyl)alkyl; haloalkyl, each or which issubstituted or unsubstituted; or R₄ is optionally substitutedcarbocyclic aryl, optionally substituted arylalkyl, or an optionallysubstituted heteroaromatic or heteroalicyclic group having from 1 to 3rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; R₃ andR_(3A) are the same or different and represent hydrogen or alkyl; or R₃and R_(3A), taken together with the carbon atom to which they areattached, form a cycloalkyl ring; R₅ and R₆ are the same or differentand represent hydrogen, halogen, hydroxy, alkyl, or alkoxy; or R₅ andR₆, taken together with the carbon atom to which they are attached forma cycloalkyl ring; R_(5a) and R_(6a) are independently selected at eachoccurrence from hydrogen, halogen, hydroxy, alkyl, and alkoxy; R₇represents hydrogen or alkyl; Ar₁ is optionally substituted carbocyclicaryl, optionally substituted arylalkyl, or an optionally substitutedheteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8members in each ring and from 1 to 3 heteroatoms; Ar₂ is optionallysubstituted carbocyclic aryl, optionally substituted arylalkyl, or anoptionally substituted heteroaryl or heteroalicyclic group having from 1to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; theprocess comprising: reacting a compound of the formula:

wherein Y is halogen or sulfonate ester, in a suitable solvent in thepresence of a suitable base, with a secondary amine of the formula:


13. A process according to claim 12, wherein n and Y are as defined inclaim 12; R₃ and R_(3A) are the same or different and represent hydrogenor C₁–C₆ alkyl; or R₃ and R_(3A), taken together with the carbon atom towhich they are attached, form a C₃₋₈ cycloalkyl ring; R₅ and R₆ are thesame or different and represent hydrogen, halogen, hydroxy, C₁–C₆ alkyl,or C₁–C₆ alkoxy; or R₅ and R₆, taken together with the carbon atom towhich they are attached form a C₃₋₈ cycloalkyl ring; R_(5a) and R_(6a)are independently selected at each occurrence from hydrogen, halogen,hydroxy, C₁–C₆ alkyl, and C₁–C₆ alkoxy; R₂ is hydrogen or C₁₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, (C₃₋₈ cycloalkyl) C₁₋₃alkyl, or C₁–C₆ haloalkyl, each of which is unsubstituted or substitutedby one or more substituents independently chosen from halogen, nitro,cyano, trifluormethyl, trifluoromethoxy, C₁₋₃ haloalkyl, hydroxy,acetoxy, alkoxy, amino, and mono- or di(C₁–C₆)alkylamino; R₄ is hydrogenor C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈cycloalkyl, (C₃₋₈cycloalkyl)C₁₋₄alkyl, or haloalkyl, each of which is unsubstituted orsubstituted with one or more substituents independently selected fromhalogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy,amino and mono- or di(C₁–C₆)alkylamino, or R₄ is phenyl,ethylenedioxyphenyl, methylenedioxyphenyl, phenylalkyl, chromanyl,pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl,pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl,indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl,benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl,quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl,each of which is optionally substituted with up to four groupsindependently selected from halogen, nitro, cyano, trifluoromethyl,trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono- ordi(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters ofcarboxylic acids, aminocarbonyl, mono or di(C₁–C₆)alkylaminocarbonyl,N—(C₁–C₆)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,1-piperidyl, —X₄R_(B), wherein X₄ and R_(B) are as defined below; or R₄is a bicyclic oxygen-containing group of the formula:

 wherein R_(A) represents from 0 to 3 groups independently selected fromhalogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy,amino, and mono- or di(C₁–C₆)alkylamino; Ar₁ is chosen from i)ethylenedioxyphenyl, methylenedioxyphenyl, phenyl, phenylalkyl,chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl,pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl,indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl,benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl,quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl,each of which is optionally substituted or substituted with up to fourgroups independently selected from halogen, nitro, cyano,trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C₁–C₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆, alkoxy, amino, mono- ordi(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, caters ofcarboxylic acids, aminocarbonyl, mono or di(C₁–C₆)alkylaminocarbonyl,N—(C₁–C₆)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,1-piperidyl, and —X₄R_(B), wherein X₄ and R_(B) are as defined below;and ii) bicyclic oxygen-containing groups of the formula:

 wherein R_(B) represents from 0 to 3 groups independently selected fromhalogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy,amino, and mono- or di(C₁–C₆)alkylamino; Ar₂ is chosen from i) phenyl,phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl,imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl,naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl,benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl,benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl,and quinoxalinyl, each of which is optionally substituted or substitutedwith up to four groups independently selected from halogen, nitro,cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy, amino, mono- ordi(C₁–C₆)alkylamino, amino(C₁–C₆)alkoxy, carboxylic acid, esters ofcarboxylic acids, aminocarbonyl, mono or di(C₁–C₆)alkylaminocarbonyl,N—(C₁–C₆)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,1-piperidyl, and —X₄R_(B), wherein X₄ and R_(B) are as defined below;and ii) bicyclic oxygen-containing groups of the formula:

 wherein R_(B) represents from 0 to 3 groups independently selected fromhalogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,hydroxy, acetoxy, C₁–C₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁–C₆ alkoxy,amino, and mono- or di(C₁–C₆)alkylamino; X₄ is independently selected ateach occurrence from the group consisting of —CH₂—, —CHR_(C)—, —O—,—S(O)_(m)—, —NH—, —NR_(C)—, —C(═O)NH—, —C(O)NR_(C)—, —S(O)_(m)NH—,—S(O)_(m)NR_(C)—, —NHC(═O)—, —NR_(C)C(═O)—, —NHS(O)_(m)—,—C(O)NHS(O)_(m)—, and —NR_(C)S(O)_(m)— wherein m is 0, 1, or 2; andR_(B) and R_(C) are independently selected at each occurrence from thegroup consisting of: hydrogen, straight, branched, or cyclic alkylgroups, which optionally contain one or more double or triple bonds,each of which is unsubstituted or substituted with one or moresubstituent(s) selected from: oxo, hydroxy, —O(C₁–C₆ alkyl), —NH(C₁–C₆alkyl), —N(C₁–C₆ alkyl)(C₁–C₆ alkyl), —NHC(O)(C₁–C₆ alkyl), —N(C₁–C₆alkyl)C(O)(C₁₋₆ alkyl), —NHS(O)_(x)(C₁–C₆ alkyl), —alkyl), wherein x is0, 1, or
 2. 14. A compound according to claim 1, wherein R₃, R_(3A), andR₇ are hydrogen; Ar₁ is phenyl, ethylenedioxyphenyl, ormethylenedioxyphenyl; Ar₂ is phenyl, ethylenedioxyphenyl, ormethylenedioxyphenyl, each of which is optionally substituted with up tofour substitutents independently selected from C₁–C₆alkyl, C₁–C₆alkoxy,halogen, hydroxy, carboxylate, and C₁–C₆alkoxycarbonyl; R₂ isC₃–C₈alkyl; R₄ is C₃–C₈alkyl, phenyl, ethylenedioxyphenyl, ormethylenedioxyphenyl, each of which is optionally substituted with up tofour substitutents selected from C₁–C₆alkyl, C₁–C₆alkoxy, halogen,hydroxy, carboxylate, and C₁–C₆alkoxycarbonyl; R₅, R_(5a), R₆ and R_(6a)are independently selected from hydrogen and C₁–C₆alkyl; and n is 0or
 1. 15. A compound of the formula:

or a pharmaceutically acceptable salt, prodrug or hydrate thereof,wherein Ar₁ is phenyl, ethylenedioxyphenyl, or methylenedioxyphenyl; Ar₂is phenyl, ethylenedioxyphenyl, or methylenedioxyphenyl, each of whichis optionally substituted with up to four substitutents selected fromC₁–C₆alkyl, C₁–C₆alkoxy, halogen, hydroxy, carboxylate, andC₁–C₆alkoxycarbonyl; R₂ is C₃–C₈alkyl; R₄ is C₃–C₈alkyl or phenyl whichis optionally substituted with up to four substitutents selected fromC₁–C₆alkyl, C₁–C₆alkoxy, halogen, hydroxy, carboxylate, andC₁–C₆alkoxycarbonyl; and R₅ and R₆ are independently selected fromhydrogen and C₁–C₆alkyl.
 16. A compound of the formula:

wherein Ar₁ is phenyl, ethylenedioxyphenyl, or methylenedioxyphenyl; Ar₂is phenyl, ethylenedioxyphenyl, or methylenedioxyphenyl, each of whichis optionally substituted with up to four substitutents selected fromC₁–C₆alkyl, C₁–C₆alkoxy, halogen, hydroxy, carboxylate, andC₁–C₆alkoxycarbonyl; R₂ is C₃–C₈alkyl; and R₄ is C₃–C₈alkyl or phenylwhich is optionally substituted with up to four substitutents selectedfrom C₁–C₆alkyl, C₁–C₆alkoxy, halogen, hydroxy, carboxylate,C₁–C₆alkoxycarbonyl.
 17. A compound of claim 1 selected from:Benzo[1,3]dioxol-5-ylmethyl-benzyl-(3-butyl-2-phenyl-4,5,6,7-tetrahydro-3H-benzoimidazol-4-yl)-amine;4-{[Benzyl-(3-butyl-2-phenyl-4,5,6,7-tetrahydro-3H-benzoimidazol-4-yl)-amino]-methyl}-3-chloro-phenol;Benzo[1,3]dioxol-5-ylmethyl-benzyl-(3-butyl-2-phenyl-3,4,5,6-tetrahydro-cyclopentaimidazol-4-yl)-amine;Benzo[1,3]dioxol-5-ylmethyl-butyl-(3-butyl-2-phenyl-3,4,5,6-tetrahydro-cyclopentaimidazol-4-yl)-amine;4-{[Butyl-(3-butyl-2-phenyl-3,4,5,6-tetrahydro-cyclopentaimidazol-4-yl)-amino]-methyl}-3-chloro-phenol;4-{[Benzyl-(3-butyl-2-phenyl-3,4,5,6-tetrahydro-cyclopentaimidazol-4-yl)-amino]-methyl}-3-chloro-phenol;4-{[Benzyl-(3-butyl-2-phenyl-3,4,5,6-tetrahydro-cyclopentaimidazol-4-yl)-amino]-methyl}-phenol;4-{[Butyl-(3-butyl-2-phenyl-3,4,5,6-tetrahydro-cyclopentaimidazol-4-yl)-amino]-methyl}-phenol;Benzo[1,3]-dioxol-5-ylmethyl-benzyl-(3-butyl-6,6-dimethyl-2-phenyl-4,5,6,7-tetrahydro-3H-benzoimidazol-4-yl)-amine;4-{[Butyl-(3-butyl-6,6-dimethyl-2-phenyl-4,5,6,7-tetrahydro-3H-benzoimidazol-4-yl)-amino]-methyl}-3-chloro-phenol;3-{[Butyl-(3-butyl-6,6-dimethyl-2-phenyl-4,5,6,7-tetrahydro-3H-benzoimidazol-4-yl)-amino]-methyl}-phenol;4-{[Butyl-(3-butyl-6,6-dimethyl-2-phenyl-4,5,6,7-tetrahydro-3H-benzoimidazol-4-yl)-amino]-methyl}-phenol;4-{[Butyl-(3-butyl-6,6-dimethyl-2-phenyl-4,5,6,7-tetrahydro-3H-benzoimidazol-4-yl)-amino]-methyl}-3-chloro-phenol;4-{[Butyl-(3-butyl-6,6-dimethyl-2-phenyl-4,5,6,7-tetrahydro-3H-benzoimidazol-4-yl)-amino]-methyl}-benzoicacid methyl ester; and4-{[Butyl-(3-butyl-6,6-dimethyl-2-phenyl-4,5,6,7-tetrahydro-3H-benzoimidazol-4-yl)-amino]-methyl}-benzoic acid.
 18. A pharmaceutical compositioncomprising a compound of claim 1 or a salt, prodrug or hydrate thereofand a pharmaceutically acceptable carrier therefor.